Hepatic encephalopathy

Etiology and risk factors: Hepatic encephalopathy constitutes a spectrum of CNS disturbances. These disturbances may appear in conjunction with severe liver injury or liver failure or after portosystemic shunt surgery. The cause of this disorder is the livers inability to metabolize ammonia to form urea so that it can be excreted. Ammonia is a CNS depressant. Changes during the initial stages of hepatic encephalopathy include reduced mental alertness, confusion, and restlessness. Loss of consciousness, seizures, and irreversible coma occur in the terminal stage. Pathophysiology: The specific cause of hepatic encephalopathy is unknown, but it is characterized by elevations of ammonia levels in the blood and cerebrospinal fluid (CSF). Ammonia is produced in the gastrointestinal tract when protein is broken down by bacteria, by the liver, and, in lesser amounts, by gastric juices and peripheral tissue metabolism. The kidneys are another source of ammonia in the presence of hypokalemia. More recently implicated as a cause of encephalopathy are false neurotransmitters, elevated levels of mercaptans (organic chemicals that contain the sulfhydryl radical, formed when the oxygen of an alcohol molecule is replaced by sulfur), phenol, and short-chain fatty acids. Normally the liver converts ammonia into glutamine, which is stored in the liver and is later converted to urea and excreted through the kidneys. Blood ammonia levels rise when the liver cells are unable to perform this conversion. Failure of the liver to perform this function may be due to liver cell damage and necrosis. It also may result from the shunting of blood from the portal venous system directly into the systemic venous circulation (bypassing the liver). In either case, as blood ammonia levels rise, many unusual compounds begin to form. Some of these compounds (e.g., octopamine) apparently act as false neurotransmitter in the CNS. Ammonia also is a CNS toxin, affecting glial and nerve cells; it leads to altered CNS metabolism and function. Any process that increases protein in the intestine, such as increased dietary protein or gastrointestinal bleeding, causes elevated blood ammonia levels and possible manifestations of hepatic encephalopathy in clients with hepatocellular failure or who have undergone portosystemic shunt surgery. HEPATIC ENCEPHALOPATHY: CAUSES OR PRECIPITATING FACTORS  Decrease in hepatocellular function  Hypoxia  Infection  Diuretics (produce hypokalemia, alkalosis, and hypovolemia)  Depressants: Phenobarbital, narcotics, tranquilizers, and sedatives  Gastrointestinal bleeding  Medications containing ammonium or amino compounds  Paracentesis  Increased protein intake  Constipation  Dehydration  Hypokalemia  Portosystemic and portacaval shunts

Clinical manifestations: The manifestations of hepatic encephalopathy are primarily neurologic and range from mild mental confusion to deep coma. The neurologic changes occur with cerebral accumulation of ammonia or gastrointestinal bleeding. Hepatic encephalopathy impairs memory, attention, concentration, and rate of response. Sleep pattern reversal often occurs, with the client awake at night and sleepy during the day. Handwriting and speech show significant changes as intellectual deterioration occurs. Asterixis may be present. In some clients with hepatic encephalopathy, hyperventilation with respiratory alkalosis develops because high ammonia levels stimulate the respiratory center the presence of methylmercaptan causes a characteristic odor on the breath called fetor hepaticus.
As the clients condition deteriorates, characteristics delta waves appear on the electroencephalogram(EEG). As the syndrome progresses, the clients level of consciousness slowly diminishes, and confusion becomes more severe; however, the level of CNS depression commonly fluctuates. Coma may eventually ensue, which deepens until there is no pain response and the reflexes, including the corneal reflex, are completely absent. Laboratory results show elevated blood ammonia and CSF glutamine levels. Although these findings help to confirm the diagnosis of encephalopathy, they are not specific to it. Monitor serum ammonia levels, electrolyte levels, blood gases, and hepatic function test results (bilirubin, albumin, prothrombin, and enzymes) throughout the course. These findings help to determine the degree of imbalance and the extent of hepatic injury.

STAGES OF HEPATIC ENCEPHALOPATHY Stage I  Fatigue  Restlessness  Irritability  Decreased intellectual performance  Decreased attention span  Diminished short-term memory  Personality changes  Sleep pattern reversal Stage II  Deterioration in handwriting  Asterixis  Drowsiness  Confusion  Lethargy  Fetor hepaticus Stage III y Severe confusion y Inability to follow commands y Deep somnolence, but arousable Stage IV o Coma o Unresponsive to painful stimuli o Possible decorticate or decerebrate posturing

Prognosis: Although intervention usually alleviates hepatic encephalopathy, the client may die of circulatory or respiratory complications, infection, or delirium and convulsions. Mortality is high among clients who progress into coma with hepatic failure. Dramatic measure may be needed to reduce toxic levels of ammonia in the blood. Such measures include hemodialysis and exchange transfusions, which involve removal and replacement of about 80% of the clients blood. A liver transplant may be performed in cases of fulminant liver failure. Medical management: Identify and treat the precipitating causes Factors that may precipitate or severely aggravate hepatic encephalopathy in clients with severe liver disease include gastrointestinal bleeding, increased dietary protein, constipation, infection, CNS-depressant drugs (e.g., opiates, benzodiazepines), and dehydration. Gastrointestinal bleeding and increased protein intake may lead to increased bacterial formation of nitrogenous compounds that induce encephalopathy. The use of CNS-depressant drugs should be avoided in these clients. Protein may be totally eliminated from the diet, with an intake of only fruit juices and IV fluids, although this radical restriction leads to catabolism of the clients own protein stores. The usual protein restriction is 20 to 40 g daily. The client with chronic hepatic encephalopathy may need to adjust to a long-term, low-protein diet (50-60g/day). Vegetable and dairy protein may be better tolerated than those in meat. A diet high in vegetables and dairy products also helps to prevent constipation, thus further reducing ammonia production. Reduce Nitrogenous Waste (ammonia) in blood and bacteria in colon Neomycin and lactulose are given to reduce bacteria in the intestinal tract. Because it is not absorbed into the circulation, neomycin exerts a powerful effect on the intestinal bacteria that are responsible for ammonia production. Undesirable side effects result from the depletion of intestinal flora (e.g., diarrhea, vitamin K deficiency). Also, because neomycin is nephrotoxic, its use must be avoided in client with renal insufficiency. Lactulose, which helps decrease blood ammonia levels by reducing absorption of ammonia, is given to clients to produce two to four stools a day. Antibiotics are administered to inhibit growth of gastrointestinal bacteria, and oral magnesium sulfate or enemas are given after hemorrhage to clean out the intestines. Maintain Fluid Volume Balance With the accumulation of fluid in the abdominal area (ascites), bleeding, and decreased fluid intake, the client may experience a fluid volume deficit. This deficit, along with electrolyte imbalance that may occur, should be corrected. IV fluids are administered, carefully monitoring the quantity and rate of administration.

Nursing management: Assessment. When working with a client susceptible to hepatic encephalopathy, use interviewing and assessment techniquest o evaluate psychophysiologic status. For example, has the clients normally neat handwriting becomes sloppy and difficult to read? Is speech slow and slurred? Observe the client for personality changes with labile feeling states, and elicit liver flap or flapping tremor(asterixis) by asking the client to dorsiflex the hand with the rest of the arm resting on the bed.(in asterixis, the hand cannot be held steady.)the nurse is often the best person to assess a change in the level of mental functioning. SAFETY ALERT: Early detection of a depressed or confused level of consciousness greatly improves the clients chances of recovery. Nursing progress notes should describe the clients behavior vividly and objectively, as in states pigeons are pecking at his bedclothes, rather than offering interpretations that may have a different meaning for each reader, such as seems more confused make ongoing neurologic checks to determine the level of consciousness and/or progression to coma.

Diagnosis, outcomes, interventions

Diagnosis: ineffective Therapeutic Regimen Management and Ineffective Family Therapeutic Regimen Management. The client and family members are vital players in the control of encephalopathy. Thus the nursing diagnoses ineffective Therapeutic Regimen Management and ineffective Family Therapeutic Regimen Management related to reduction in protein in the diet and long-term pharmacologic intervention with neomycin are common with hepatic encephalopathy. Outcomes: the client will understand and comply with the reduction of protein in the diet and long-term pharmacologic intervention with neomycin as evidenced by the clients following a low-protein diet and stating reasons why neomycin should be taken. Interventions: Promote Low-protein diet. It is important that the client understand the importance of the reduced protein diet to have the motivation to remain on this diet. Monitor for Gastrointestinal Hemorrhage. In addition to ensure a low-protein diet, assess for manifestations of gastrointestinal bleeding, checking fir bright red blood in the stool or for black, tarry stools. To reverse the progression of manifestations, constipation must be prevented. Administer cathartics and enemas to hasten the exit of protein material from the intestines. Encourage bowel cleansing. The client may need to learn to manage diarrhea, a possible side effect related to the laxative action of lactulose or neomycin sulfate. Intervention in severe hepatic encephalopathy commonly combines neomycin and provide a low-protein diet for clients with chronic hepatic encephalopathy. In addition, administer oral lactulose, a combination of galactose and fructose that passes through the intestine unchanged, to decrease ammonia by trapping ammonium ions and allowing their evacuation from the bowel. As noted earlier, the

appropriate lactulose dosage causes two to four soft stool evacuations daily. If severe diarrhea occurs, the dosage is reduced to prevent further electrolyte imbalance.

Diagnosis: deficient fluid volume: the client often has difficulties with fluid volume,
leading to the nursing diagnosis deficient fluid volume related to bleeding, decreased intake, and ascites. Outcomes: the client will maintain a balanced flid volume, as evidenced by normal blood pressure, absence of edema, absence of ascites, and balanced intake and output. Intervention: hypovolemia often precipitates hepatic encephalopathy by reducing hepatocellular perfursion. Fluid balance must be achieved, maintained, and monitored to prevent further hepatic injury and reduced renal perfusion. Deliver IV fluids evenly over time. Monitor vital signs frequently. If necessary, measure urine output hourly. Electrolyte and acid-base disturbances such as hypokalemia and alkalosis may precipitate hepatic encephalopathy or may develop during its course. Laboratory tests indicate which replacement therapy is necessary.

Diagnosis: risk fir injury. Because of the multitude of problems faced by the client with
encephalopathy, the nursing diagnosis risk for injury related to loss of protective mechanisms secondary to hepatic coma is common. Outcome. Injury or complications of immobility will be prevented or will be identified early as evidenced by the absence of problems related to immobility. Intervention. Hepatic coma may create a multitude of problems for the client with encephalopathy. Prevent hypoxemia. Hypoxemia may precipitate hepatic encephalopathy by damaging the hepatic cell. SAFETY ALERT: to prevent and treat hypoxemia, attend to respiratory interventions (e.g., maintain a patent airway). Prevent infection. Concurrent infection, with accumulation of protein from tissue catabolism, necessitates rapid intervention. SAFETY ALERT: the client is particularly vulnerable to nosocomial(hospital-acquired) infections. Wash your hands thoroughly, and take other measures to prevent cross contamination. Prevent ammonia. Toxicity and hypokalemia SAFETY ALERT: be alert to possible harmful accumulations of ammonia as a result of diuretic therapy. Hypokalemia from the use of diuretics contributes to hepatic encephalopathy by increasing ammonia production in the kidney. Avoid sedation SAFETY ALERT: agents with CNS-depressant effects may precipitate coma, and there should thus be avoided. If agitation occurs in early encephalopathy, administer agents that are excreted partially through the kidney, instead of the liver (e.g., Phenobarbital).

Administer Phenobarbital with caution. Know which opioids, tranquilizers, and sedatives are biotransformed by the liver; they are often contraindicated in clients with decreased hepatic function. Prevent complications of immobility. The immobile client who lacks protective reflex (blink or gag reflex) is vulnerable to numerous complications. Preventing complications requires intensive nursing intervention. Prevent pneumonia and skin breakdown by turning the client frequently and promoting lung aeration. As the body accumulates metabolic substances, physiologic disturbances develop that may produce a state of agitation. SAFETY ALERT: therefore protect the client from self-injury, for example, by lowering the bed and padding the side rails. Evaluation. The prognosis for the client with hepatic encephalopathy is poor. Generally the best outcone that can be hoped for is maintenance with slowed deterioration.

For Self Care:

Medications: review all medications along with scheduled times of administration and
their intended and adverse side effects. Potential medications include lactulose, diuretics, and vitamin supplements.

Diet modifications: explain the importance of a well-balanced, nutritional diet to the

client, with specific information about limitations on dietary protein, sodium, and water. Teach family members and significant others about the need to encourage eating and still maintain food intake within prescribed limits.

Home modification: teach that the clients home may need to be altered to adjust for
limitations in mobility. Safety precautions should be taken to help prevent injury to the client. The clients bedroom should be near the bathroom if the client is receiving diuretics.

Reference: MS book 8th Edition

Hepatic Encephalopathy Also known As Hepatic Coma

Submitted to: Ms. Michelle Basilio-Estillore RN

BSN 4A clinical instructor

Submitted by: John Cyril G. Ramos

I have read a case about this case about an old woman who was admitted at the hospital with the case hepatic encephalopathy, this story was diagnosed in the year 1997 and this is her diagnosis and other details. A 68-year-old woman was admitted to the hospital because of hepatic encephalopathy. The patient had been well until several years earlier, when she began to gain weight and experience exertional dyspnea. Fourteen months before admission, her cholesterol level was 270 mg per deciliter (6.98 mmol per liter), and her high-density lipoprotein cholesterol level was 57 mg per deciliter (1.47 mmol per liter). A cardiac ultrasonographic examination showed normal left ventricular size and function. The results of liver-function tests were slightly abnormal. A dipyridamolethallium stress test with exercise showed a 1-mm horizontal ST-segment depression in the apical and inferior leads; the radionuclide scan showed normal left ventricular perfusion. Ten months before the current admission, laboratory tests were performed Nine and a half months before the current admission, she entered this hospital. The patient was a secretary. She had long-standing, nondeforming rheumatoid arthritis, which had been treated with gold many years earlier. Fifteen years before admission, severe epistaxis required transfusions, arterial ligation, and insertion of a metal plate in the nose. Six years before the current admission, a cholecystectomy was performed because of multiple gallstones with biliary colic. Between 3 1/2 years and 5 months before admission, 1250 mg of methotrexate was administered, but the treatment was discontinued because of a pruritic rash. During the few years before admission, the patient's weight had increased from 77.3 to 88.6 kg. There was no history of liver disease or anemia or use of alcohol, illicit drugs, or nonsteroidal antiinflammatory drugs. There was no family history of anemia or liver disease. The patient's current medications were furosemide and a potassium supplement. The results of an examination at this hospital were normal except that the liver edge was palpable at the right costal margin, with a span of 9 cm. Laboratory tests were performed. An ultrasonographic examination of the abdomen showed fatty changes in the liver. The results of an osmotic-fragility test with an incubated blood sample were normal; there was no evidence of hemolysis. The protease-inhibitor type was probably PZ. The patient declined a needle-aspiration biopsy of the liver and did not return for a follow-up evaluation. Ten days before admission, she entered another hospital because of increasing dyspnea with peripheral edema. An examination showed that the blood pressure was 160/60 mm Hg. The jugular venous pressure was normal. Crackles were heard at both lung bases, and a grade 2 systolic murmur was present along the left sternal border. There was +++ peripheral edema. The urine was normal. Laboratory tests were performed .Radiographs of the chest showed evidence of early congestive heart failure, an old vertebral fracture at T12, and new compression fractures at T8 and T9. A cardiac ultrasonographic study revealed left atrial enlargement and mild mitral regurgitation; the left ventricle was normal, with an ejection fraction of 70 percent. Furosemide was given intravenously, with resolution of the edema. On the eighth hospital day, the patient was transferred to a rehabilitation facility, receiving conjugated estrogens, furosemide (80 mg daily), potassium chloride, calcium carbonate, ibuprofen, and propoxyphene. Three days later, she vomited green bilious liquid on two occasions and became increasingly lethargic. The ammonia level was 131 mol per liter. She was transferred to this hospital.

The temperature was 36C, the pulse was 83, and the respirations were 20. The blood pressure was 135/50 mm Hg. On examination, the patient was obese and lethargic. There was mild sclera icterus. No rash, spider angioma, or lymphadenopathy was found. A few crackles were heard at both lung bases. A grade 3 systolic murmur was present at the cardiac apex and left sternal border. The liver edge was palpated at the right costal margin; the spleen was not felt, and no evidence of ascites was detected. A stool specimen was positive (+) for occult blood. On neurologic examination, the patient responded to voice but obeyed no commands. Asterixis was present. No focal signs were found. The urine was normal except for a trace-positive test for urobilinogen. Laboratory tests were performed. A screening test of serum for substances of abuse was negative except for the presence of propoxyphene. A specimen of gastric contents obtained through an orogastric tube contained coffee grounds material. An electrocardiogram showed a normal rhythm at a rate of 90, with minor ST-segment and T-wave abnormalities. A radiograph of the chest showed low lung volumes, pulmonary edema, and a small left pleural effusion. The vascular pedicle was widened, and the heart was enlarged. Specimens of blood and urine were sent for culture. Cimetidine, vitamin K, lactulose, thiamine, and multivitamins were given, and ampicillin and ceftriaxone were administered intravenously. After the intravenous administration of fresh-frozen plasma, a lumbar puncture was performed During the next several days, the patient became more alert. Abdominal radiographs showed mild osteopenia with a wedge-compression fracture at T12. An ultrasonographic study of the abdomen. showed diffuse, heterogeneous hyperechogenicity of the liver, suggesting fatty change. By the fourth hospital day, the patient was drowsy. The platelet count was 56,000 per cubic millimeter. The ammonia level was 49 g per deciliter (29 mol per liter). All bacteriologic cultures were negative. Antibiotics were discontinued; a heparin lock was removed, and omeprazole was substituted for cimetidine. A computed tomographic (CT) scan of the liver showed a right pleural effusion and ascites with an attenuation value of 26.1 Hounsfield units. Doppler ultrasonography showed mild mitral regurgitation and trace tricuspid regurgitation. The left atrium was dilated, and the mitral inflow pattern showed a dominant A wave when the E and A waves were not fused, a finding consistent with diastolic dysfunction. There was reversal of diastolic flow in the pulmonary venous inflow pattern, a finding consistent with elevated left atrial pressure. The left ventricle was hyperkinetic, and the estimated ejection fraction was 79 percent. The pulmonary artery was dilated. The right ventricle appeared normal. On the seventh hospital day, the patient was fully alert and oriented, and there was no asterixis. A diagnostic procedure was performed. Differential Diagnosis Dr. Carl L. Berg*: May we review the radiographs? Dr. J. Mark Ryan: A chest radiograph obtained on admission shows cardiac enlargement, a widened vascular pedicle, prominent pulmonary vessels, pulmonary edema, and a left pleural effusion. An abdominal film obtained at the same time shows generalized osteopenia and a wedge-compression fracture of T12. The abdominal ultrasonographic study reveals hyperechogenicity of a normal-sized liver, which is diffusely heterogeneous, a finding consistent with either fatty change or hemochromatosis. The CT scan of the liver shows a low level of

attenuation and a measurement of 26.1 Hounsfield units. Ascites is present, as are bilateral pleural effusions. The biliary ducts appear normal. Dr. Berg: I shall focus on the patient's history, since hepatic encephalopathy associated with the administration of opioids and gastrointestinal bleeding is consistent with any form of chronic liver disease. She had slightly elevated aspartate aminotransferase and alkaline phosphatase levels for at least 10 months before progressive hepatic synthetic dysfunction developed. She also had dyspnea, a poorly characterized arthritis treated with methotrexate, a macrocytic anemia, pronounced osteopenia complicated by multiple vertebral fractures, and echocardiographic evidence of ventricular diastolic dysfunction. In addition, she was obese, had undergone a cholecystectomy 6 years before the current admission, and had received transfusions 15 years earlier. Several causes of chronic liver disease can be ruled out immediately. The serologic values fail to support a diagnosis of chronic hepatitis B infection. The patient reported that she did not consume alcohol. Primary biliary cirrhosis, although occurring predominantly in people in her age group, is characterized by laboratory evidence of cholestasis and a positive antimitochondrial-antibody test in over 95 percent of the cases. The absence of symptoms of inflammatory bowel disease, the patient's sex, and the minimal elevation in the alkaline phosphatase level are strong evidence against sclerosing cholangitis. Despite the history of a cholecystectomy, it is difficult to entertain the diagnosis of a biliary complication leading to biliary cirrhosis, which should be associated with laboratory evidence of cholestasis and extrahepatic bile-duct dilatation on abdominal imaging. Lastly, the initial presentation of Wilson's disease in a 68-year-old person would be exceedingly uncommon. Could steatohepatitis have caused this patient's progressive liver disease? Several of the findings are consistent with this disorder: obesity and hyperlipidemia are risk factors for nonalcoholic steatohepatitis, and slightly elevated aspartate aminotransferase and alanine aminotransferase levels are characteristic. Moreover, histologic evidence of progressive liver disease has been detected in up to 36 percent of patients with steatohepatitis. Progression to end-stage liver disease is uncommon, however, and steatohepatitis would not explain the cardiac, rheumatologic, or bone findings. Liver damage due to methotrexate therapy has been observed most often in patients with psoriatic arthritis, although it has also been documented in smaller numbers of patients with rheumatoid arthritis.The age of the patient and the duration of therapy are independent risk factors for clinically important liver disease in patients with rheumatoid arthritis who are taking methotrexate. Although this patient's age is a risk factor, a 1250-mg dose of methotrexate is less than the amount typically associated with serious liver injury. Obesity, which is present in this case, and diabetes and alcohol intake, which are not, are also risk factors for methotrexate hepatotoxicity, although they are more important in patients with psoriatic arthritis than in those with rheumatoid arthritis. A recent report of the development of methotrexate hepatotoxicity in a patient with the MZ phenotype of alpha1-antitrypsin deficiency raises the possibility that methotrexate therapy in such a patient confers a predisposition to liver disease. Thus, although methotrexate is unlikely to have been the primary cause of this patient's liver failure, it may have had a contributory role. The American College of Rheumatology recommends that aspartate and alanine aminotransferase and serum albumin levels be monitored every four to eight weeks during the administration of methotrexate. Furthermore, a low serum albumin level, such as this patient had during methotrexate therapy, is an indication for liver biopsy, because it strongly indicates

hepatotoxicity. If the patient refuses a biopsy, as this patient did, discontinuance of the therapy is recommended. Although the diagnosis of autoimmune hepatitis should be strongly considered in a woman of this patient's age, the low titers of antinuclear and antismooth-muscle antibodies, along with the clinical findings and other laboratory values, would not meet the criteria for definite autoimmune hepatitis as set forth by a recent consensus panel but might meet the criteria for probable autoimmune hepatitis. Making this diagnosis, however, requires that all other possible causes of liver disease be ruled out. Furthermore, autoimmune hepatitis would not explain the extrahepatic findings in this case. Can we link the patient's liver disease to the transfusions she received 15 years ago? Screening of the blood supply for hepatitis C was not available at that time, and thus chronic hepatitis C infection could have developed. The antibody test for hepatitis C was negative, however, and with the use of second-generation enzyme-linked immunosorbent assays for the detection of hepatitis C infection, false negative findings are rare. The long interval between the transfusions and the patient's current illness is compatible with chronic hepatitis C infection, as are the low aspartate aminotransferase and alanine aminotransferase levels. Immunoblot radioassays and polymerase-chain-reaction assays for the detection of hepatitis C RNA are available. Negative results of these tests would have ruled out chronic hepatitis C infection more definitively. Today one must also entertain the possibility of blood-borne exposure to hepatitis G infection. Relatively little is known about the typical clinical course of this recently described viral infection, and testing for its detection is not yet readily available. However, neither hepatitis C infection nor hepatitis G infection would explain the cardiac, rheumatologic, or bone abnormalities in this patient. It is time to consider the diagnosis of choice. The iron level of 164 g per deciliter (29.4 mol per liter) and the total iron-binding capacity of 169 g per deciliter (30.3 mol per liter) 9 1/2 months before admission yield a transferrin saturation of 97 percent, which along with the serum ferritin value of 634 ng per milliliter, suggests iron overload as a possible cause of this patient's chronic liver disease. Although her anemia and low haptoglobin levels raise the possibility of hemolysis and thus secondary iron overload, macrocytic anemia and low haptoglobin values are typical of chronic liver disease, and the results of the direct Coombs' and osmotic-fragility tests were normal. In the absence of hemolysis or a history of numerous blood transfusions, these iron studies strongly support the diagnosis of genetic hemochromatosis. This autosomal recessive disorder, characterized by excessive intestinal iron absorption, results in iron deposition in the liver, pancreas, myocardium, and joints, with cellular injury mediated by free radicals. This patient has many of the clinical features of hemochromatosis. Her age at presentation is typical of women with this disease, which develops 10 years later in women than in men, presumably because of iron loss during menses and childbirth. The insidious onset of this patient's disease is also characteristic, with her hepatic decompensation attributable to the progressive development of cirrhosis caused by continuous accumulation of hepatocellular iron. Cardiac dysfunction in association with hemochromatosis varies considerably. There may be no clinical or echocardiographic evidence of cardiac involvement. Dilated cardiomyopathy is the most frequent abnormality. However, restrictive cardiomyopathy may also be demonstrated echocardiographically and may precede dilated cardiomyopathy. The diastolic dysfunction, left atrial enlargement, and preserved right ventricular function noted in this patient are all compatible with early cardiac dysfunction in association with hemochromatosis.

Little information is provided about the joint involvement, serologic values, and findings on physical examination that supported the diagnosis of rheumatoid arthritis in this case, raising the question whether the joint disease may also have been due to hemochromatosis. Over half the patients with hemochromatosis who are not identified by family screening have arthropathy, which may precede the diagnosis of hemochromatosis by many years. The manifestations include involvement of the metacarpophalangeal and proximal interphalangeal joints, hips, knees, and shoulders. Joint inflammation may be minimal or extensive and may mimic either rheumatoid arthritis or osteoarthritis. Since there are findings characteristic of hemochromatosis on films of the hands, it would be helpful to review any such films in this case. The abdominal films do not reveal intervertebral chondrocalcinosis, which has been reported in a minority of cases of hemochromatosis. The anterior wedge deformity suggests that the vertebral fractures were caused by osteopenia and not a nonhepatic malignant tumor, even though hemochromatosis may confer a predisposition for such tumors. Although osteoporosis is more typically associated with chronic cholestatic liver diseases, patients with hemochromatosis are also at increased risk for its development. Thus, this patient's osteoporosis is a consequence of her age, sex, and hemochromatosis. The transferrin saturation of 97 percent is within the range of 55 to 100 percent reported for index patients with hemochromatosis but is not typical of those who are heterozygous for hereditary hemochromatosis, who have lower values. A definitive diagnosis of hemochromatosis, however, cannot be made on the basis of serum chemical values alone. Confirmation of the diagnosis depends on the hepatic iron concentration and the hepatic iron index. Only two features of this case are inconsistent with a diagnosis of homozygous hemochromatosis as the sole cause of this patient's liver disease: the markedly elevated aspartate aminotransferase level during her current admission and the hepatic attenuation value of only 26.1 Hounsfield units on abdominal imaging, which is well below the level of 70 or higher typically associated with symptomatic hemochromatosis. Intrahepatic fat, however, lowers the attenuation level, and there are at least three reports of false negative findings on abdominal CT scans in patients with documented iron overload due to hemochromatosis and simultaneous steatosis. Thus, I am not dissuaded by the normal attenuation value in an obese patient who is heterozygous for alpha1-antitrypsin deficiency and has also received methotrexate; both obesity and methotrexate therapy may lead to hepatic steatosis.The more marked elevation in the aspartate aminotransferase level during her current admission is occasionally observed with hemochromatosis but may also reflect heterozygosity for alpha1-antitrypsin deficiency. Alpha1-antitrypsin is the primary inhibitor of neutrophil elastase. There are over 75 known variants of the alleles for this protein, which are named according to the position of migration of the alpha1-antitrypsin molecule on isoelectric-focusing gels.The common normal alleles are designated M. The most common abnormal alleles, designated Z and S, confer an increased risk of emphysema when present in the homozygous state. Chronic liver disease develops in persons who are homozygous for the Z allele or the uncommon NullHong Kong, Mmalton, or Mduarte alleles. The mechanisms involved in the development of liver disease in ZZ homozygotes have been at least partially delineated. The Z mutation results in a single-base substitution in exon V of the most common M allele, M1, causing the substitution of lysine for glutamate at position 342 in the alpha1-antitrypsin molecule. This substitution reduces the stability of alpha1-antitrypsin monomers and favors the generation of alpha1-antitrypsin polymers in the endoplasmic reticulum of the hepatocyte, where alpha1-antitrypsin is synthesized. Accumulation of this mutant alpha1antitrypsin molecule results in liver disease by undefined mechanisms. Recent studies have demonstrated that in persons with the ZZ mutation in whom liver disease develops, there is also a lag in the degradation of the mutant molecule in the endoplasmic reticulum, which can exacerbate the liver injury.

Whether persons with the MZ protease-inhibitor type are at increased risk for liver disease is a matter of controversy. Globules that are positive for periodic acidSchiff and resistant to diastase, which are characteristic of alpha1-antitrypsin, may be seen in liver specimens from patients with MZ, but most of these patients do not have clinically important liver disease. To date, the rare P family of alpha1-antitrypsin alleles has not been associated with the development of liver disease, even when the P allele occurs in conjunction with the Z allele. At least eight P variants have been described. The Plowell mutation results in a protein that is rapidly degraded within the hepatocyte, resulting in low levels of serum alpha1-antitrypsin. Patients with this mutation are at risk for emphysema. A detailed analysis of the hepatocellular fate of alpha1antitrypsin molecules produced by other P variants has not yet been performed. What clinical sequelae may this patient have had as a result of her PZ alpha1-antitrypsin phenotype? We have no additional information to determine which variant of the P allele she had. For the best-characterized P variants, Plowell and Psaint albans, persons with the PZ phenotype have a risk of liver disease similar to that for persons with the more common MZ phenotype. Very few patients with the PZ phenotype have been studied, however, and none of them have had concomitant liver disease, such as hemochromatosis. In this patient, hepatocellular injury from iron overload may have increased steady-state levels of abnormally folded Z alpha1antitrypsin in the hepatocyte endoplasmic reticulum, initiating further hepatotoxic changes. In this situation, a patient who is heterozygous for the Z mutation might have a large accumulation of alpha1-antitrypsin in the endoplasmic reticulum, resulting in an exacerbation of the liver disease. I suspect that there is evidence of alpha1-antitrypsin accumulation in the endoplasmic reticulum of hepatocytes from this patient and that the PZ protease-inhibitor type contributed to the progression of her liver disease, but it is unlikely that the PZ phenotype was the sole cause of her hepatic decompensation. One must also consider the possible pulmonary consequences of this patient's PZ phenotype. Without subclassifying the PZ phenotype, one cannot quantify the risk of associated emphysema. The patient's dyspnea several years before this admission may have been an early manifestation of emphysema, and the pulmonary-artery dilatation may have been due to the emphysema. There were no bibasilar emphysematous changes on the chest film, however, as would be expected in lung disease associated with alpha1-antitrypsin deficiency. In conclusion, I believe that the primary cause of this patient's liver disease is hemochromatosis resulting in hepatic encephalopathy in the setting of opioid administration and gastrointestinal hemorrhage. The presence of the PZ alpha1-antitrypsin phenotype and the methotrexate therapy may have contributed to her liver disease. I believe that the diagnostic procedure was a liver biopsy. To confirm the diagnosis of homozygous hemochromatosis, a portion of the biopsy specimen should have been sent for a quantitative iron determination, in order to calculate the hepatic iron index. Dr. Lawrence S. Friedman: I cared for this patient. The findings suggested that multiple factors contributed to her liver disease, including alpha1-antitrypsin deficiency, genetic hemochromatosis (or possibly the heterozygous state and secondary iron overload), and methotrexate therapy. Because of the apparent heart failure, we considered the possibility that hemochromatosis involved the heart but were unable to demonstrate any objective abnormalities. We also wondered whether the lung dysfunction could have resulted from the alpha1-antitrypsin deficiency, but the patient did not undergo pulmonary-function testing, and there was no radiographic evidence of emphysema.

Clinical Diagnoses Hemochromatosis (or the heterozygous state). Alpha1-antitrypsin deficiency. Liver damage due to methotrexate therapy. Dr. Carl L. Berg's Diagnoses Genetic hemochromatosis. PZ heterozygosity for alpha1-antitrypsin deficiency. Pathological Discussion Dr. Fiona M. Graeme-Cook: The diagnostic procedure was a liver biopsy. Microscopical examination of the specimen revealed micronodular cirrhosis. The hepatocytes within the nodules contained prominent intracytoplasmic hyaline globules of various sizes, especially in the paraseptal regions. The globules were strongly positive on periodic acidSchiff staining and were shown immunohistochemically to contain alpha1-antitrypsin. Some hepatocytes contained small amounts of fat. The fibrous septa contained a polymorphous chronic inflammatory infiltrate with considerable bile-duct proliferation. Special staining showed fine iron granules within many hepatocytes but not in reticuloendothelial cells. The liver contained 74 mol of iron per gram; when divided by the patient's age, this value yields an index of just over 1, which is within the typical range for heterozygotes. The hepatic findings are consistent with the PZ phenotype combined with the heterozygous phenotype for genetic hemochromatosis. The absence of anisonucleosis makes the contribution of methotrexate to the steatosis uncertain. Shortly after the biopsy, the patient died, and an autopsy was performed. The only other organs that contained iron were the pancreas and adrenal glands. The heart was enlarged, with left ventricular hypertrophy. Focal bronchopneumonia was present. Mild bilateral centriacinar emphysema involved mainly the upper lobes but was not typical of emphysema caused by alpha1-antitrypsin deficiency. The histologic hallmark of alpha1-antitrypsin deficiency in the liver is the presence of intrahepatocytic globules that are positive on periodic acidSchiff staining. Such globules are seen, however, only with the protease-inhibitor Z, Mmalton, Mduarte, and NullHong Kong alleles. Several studies have assessed the frequency of liver disease in persons with alpha1-antitrypsin deficiency. One large prospective study found that neonatal hepatitis developed in 11 percent of infants with the ZZ protease-inhibitor phenotype; 25 percent of these infants had end-stage liver disease by the second decade of life, and a similar proportion recovered from the hepatitis. A small percentage of patients with the ZZ phenotype present in adolescence with hepatomegaly and abnormal liver function, and others present in adulthood with cirrhosis or chronic liver disease. Idiopathic hemochromatosis is an autosomal recessive disorder, and the gene for the disorder is present in more than 10 percent of the white population in the United States. The histopathological hallmark of hemochromatosis is the presence of coarse granular iron in

hepatocytes, with cirrhosis in homozygotes. Fibrosis does not occur in heterozygotes until hepatic iron levels exceed 400 mol per gram of dry weight. Although the mechanism whereby iron overload causes liver fibrosis is uncertain, the accumulation of iron within lysosomes may make them fragile. Since the frequency of the genes for both conditions is high, their coexistence may be relatively frequent. A heterozygous state for both conditions may accelerate the development of liver disease, but there are no data on liver changes in patients who are heterozygous for both abnormal genes. In this patient, there is clear evidence of alpha1-antitrypsin accumulation in hepatocytes in association with the PZ phenotype. The iron studies plus the presence of small amounts of iron in the pancreas and adrenal glands at autopsy indicate a heterozygous phenotype for genetic hemochromatosis. The levels of iron in the liver were not high enough to cause fibrosis. No data are available, however, to determine whether this amount of iron in the liver, combined with the alpha1-antitrypsin disease, accelerated the liver disease. Anatomical Diagnoses Alpha1-antitrypsin deficiency, PZ phenotype. Genetic hemochromatosis, heterozygous phenotype. Micronodular cirrhosis of the liver. Addendum Dr. Berg: Since the evaluation of the patient in this case, a candidate gene for hereditary hemochromatosis, termed HLA-H, has been identified. Although its function remains uncertain, preliminary investigations indicate a strong correlation between a substitution of tyrosine for cysteine at position 282 of the gene product of HLA-H and the clinical diagnosis of hereditary hemochromatosis. Studies of the frequency of homozygosity for this mutation in large populations of patients are under way. It is possible that in the future, the evaluation of patients suspected to have hereditary hemochromatosis may include genetic testing for HLA-H mutations. This case shows that even though you have no history of any liver disease or anemia still you can get this disease, if you are obese and have hyperlipidemia as the risk factors, we still can get this disease. We can also see that everything examined to her at first are normal except for a palpable liver a 9 cm span and diagnosed that she has fatty changes in her liver. And further on many signs of this disease have shown and some says that her operations for the past years are ones who triggers the hepatic encephalopathy.
This case I have found and read is actually from the internet but it is fascinating on how this disease spread, I include this in my research for us to know the real thing that is happening to patients with hepatic encephalopathy and be aware on things that may be a cause hepatic encephalopathy. This is the site where I have read the story: http://www.nejm.org/doi/full/10.1056/NEJM199703273361308
You can read her story with the figure/pictures of the results and the diagrams of the findings I also read the stories here in this site, Its really touching how these people managed their lives with this form of disease.

http://www.mdjunction.com/health-topics/hepatic-encephalopathy