CPC Case #1

(Reseach)

Gamma-glutamyl transferase (GGT) is an enzyme that is found in many organs throughout the body, with the highest
concentrations found in the liver. Normally, GGT is present in low levels, but when the liver is injured, the GGT level can rise.
GGT is usually the first liver enzyme to rise in the blood when any of the bile ducts that carry  bile from the liver to the intestines
become obstructed, for example, by tumors or stones. This makes it the most  sensitive liver enzyme test for detecting bile duct
problems. GGT is elevated in the blood in most diseases that cause damage to the liver or bile ducts. An elevated ALP with a
high GGT level helps rule out bone disease as the cause of the increased ALP level. An elevated ALP with a low or normal GGT
means the increased ALP is more likely due to bone disease. An elevated GGT level suggests that a condition or disease is
damaging the liver but does not indicate specifically the cause of the damage. In general, the higher the level, the greater the
damage to the liver. Elevated levels may be due to liver diseases, such as hepatitis or cirrhosis, but they may also be due to
other conditions, such as congestive heart failure, metabolic syndrome, diabetes, or pancreatitis. They may also be caused by
alcohol abuse, alcoholic liver disease, or use of drugs that are toxic to the liver

Domingo et al. Miliary Tuberculosis Induced Acute Liver Failure. Case Reports in Infectious Diseases.
Hindawi Journal. 2015.SN-2090-6625.DO-10.1155/2015/759341. Retrieved at
https://doi.org/10.1155/2015/759341
Wu, Z., Wang, W. L., Zhu, Y., Cheng, J. W., Dong, J., Li, M. X., Yu, L., Lv, Y., & Wang, B. (2013).
Diagnosis and treatment of hepatic tuberculosis: report of five cases and review of literature. International
journal of clinical and experimental medicine, 6(9), 845–850.

Differential Diagnosis

1. Hodgkin’s Lymphoma - is a localized or disseminated malignant proliferation of cells of the

lymphoreticular system, primarily involving lymph node tissue, spleen, liver, and bone marrow.
It results from the clonal transformation of cells of B-cell origin, giving rise to pathognomic
binucleated Reed-Sternberg cells. The cause is unknown, but genetic susceptibility and
environmental associations; history of treatment with phenytoin, radiation therapy, or
chemotherapy; and certain infections play a role. It registered 79,990 new cases (accounting for
0.4% of all new tumors) and 26,167 deaths (accounting for 0.3% of all cancer deaths) worldwide
in 2018 (Journal of Hematology and Oncology, 2019).

Rule In Rule Out

19 y/o, male (-) personal or family history of malignancies
(+) intermittent fever (-) cervical lymphadenopathies
(+) weight loss (-) pruritus
(+) generalized body weakness Additional evidence needed:
(+) hepatosplenomegaly  Liver biopsy
(+) anemia
(+) leukopenia
PT: 17.8 secs (prolonged)
 INR: 1.32
(+) hypoalbuminuria
Abd UTZ: (+) minimal ascites

Hodgkin lymphoma is a localized or disseminated malignant proliferation of cells of the lymphoreticular

system, primarily involving lymph node tissue, spleen, liver, and bone marrow. Symptoms typically
include painless lymphadenopathy, sometimes with fever, night sweats, unintentional weight loss,
pruritus, splenomegaly, and hepatomegaly. Diagnosis is based on lymph node biopsy. Treatment is
curative in most cases and consists of chemotherapy with or without other treatment modalities,
including antibody-drug conjugates, immunotherapy, and radiation therapy.

19 y/o, male - According to a study in Singapore cited by Bassig et al (2016), it showed a

continuous increase in the incidence of HL for the young age groups for men at incidence rates
increased annually by 7.0 and 3.4 % in the age groups 15–19 and 20–24 years, respectively. This
was supported by Zhou et al. (2019) citing epidemiological studies indicating HL as the most
common cancer among youngsters aged 15–19 years in the US. Meanwhile, the ACS Journals in
2017 published a study that revealed HL has striking gender predilection for males, who
make up approximately 75% of all patients diagnosed with the disease.

(+) intermittent fever – RS cells accumulate within the lymphoid tissue (<2% of total node
volume) and secrete cytokines.  A plain old intermittent fever is seen in about 35 percent of
people with Hodgkin lymphoma (Very well health. Mallick and Paul, 2020)

(+) weight loss-– RS cells accumulate within the lymphoid tissue (<2% of total node volume) and
secrete cytokines.

(+) generalized body weakness-– RS cells accumulate within the lymphoid tissue (<2% of total
node volume) and secrete cytokines.

(+) hepatosplenomegaly- reactive WBCs further support RS cell accumulations which typically
spread in an orderly way, anatomically adjacent lymph tissue outside of the lymph nodes. Extra-
nodal tissue formed can involve the spleen (occurs first), infiltration of the liver or the bone
marrow. A case report published in Turkey in 2004 detected liver involvement in 24% of patients
with HL.

Rule out

Liver biopsy --- Histological examination of the liver showed portal based infiltration of atypical
large mononuclear Hodgkin’s cells with prominent eosinophilic nucleoli and typical Reed
Sternberg cells in the context of the haphazardly arranged spindle cells and capillaries with
lymphohistiocytic background.
 HEPATIC TB

The incidence of hepatic TB remains unknown, likely due to unfamiliarity of the disease, since
historically most hepatic TB was diagnosed upon surgery or autopsy ---  The nodular form of local hepatic
tuberculosis. A review.Oliva A, Duarte B, Jonasson O, Nadimpalli V J Clin Gastroenterol. 1990 Apr;
12(2):166-73.

Poor prognostic factors included age <20 years, miliary TB, predisposing factors (treatment with
steroids, chronic renal failure, diabetes, systemic lupus erythematosus, and significant alcohol intake),
coagulopathy, low prothrombin index, and greater extent of caseation on histology -----Essop AR,
Posen JA, Hodkinson JH, Segal I. Tuberculosis hepatitis: a clinical review of 96
cases. QJM.  1984;53:465–477. [PubMed] [Google Scholar] [Ref list]

Hematogenous dissemination, or miliary disease, from a pulmonary focus is the most common etiology
of hepatic TB --Hersch C. Tuberculosis of the liver: a study of 200 cases. S Afr Med J.  1964;38:857–
863. [PubMed] [Google Scholar] [Ref list]

The source of miliary dissemination may be from another extrapulmonary site, such as an abdominal
lymph node, but this is rare. In miliary hepatic TB, bacilli reach the liver via the hepatic artery----
Hepatobiliary tuberculosis. Chong VH, Lim KS Singapore Med J. 2010 Sep; 51(9):744-51.

Miliary hepatic TB is characterized by diffuse seeding of the liver with tubercles ranging from 0.6 to
2.0 mm in diameter situated in the lobules of the liver--- Hersch C. Tuberculosis of the liver: a study of
200 cases. S Afr Med J. 1964;38:857–863. [PubMed] [Google Scholar] [Ref list]

Summary of the literature and our data, the following conditions should be suspected hepatic TB: (1)
previous medical history of tuberculosis or contact with tuberculosis and complaint mild fever, night
sweat, fatigue, weight loss, epigastric pain, jaundice, hepatomegaly with or without splenomegaly or
lymphadenopathy, liver tenderness; (2) an elevated levels of ESR, ALP, serum globulin, adenosine
deaminase but normal transaminase; positive tuberculin test; (3) US and CT scan showed intrahepatic
hypodense lesions or associated with point linear high-density calcific lesions, enhanced CT may reveal
slightly enhance. ---Wu, Z., Wang, W. L., Zhu, Y., Cheng, J. W., Dong, J., Li, M. X., Yu, L., Lv, Y., &
Wang, B. (2013). Diagnosis and treatment of hepatic tuberculosis: report of five cases and review of
literature. International journal of clinical and experimental medicine, 6(9), 845–850.

The characteristic histological feature of both miliary and local forms of hepatic TB is the granuloma--
Hepatic granulomas: a clinicopathologic analysis of 86 cases.Turhan N, Kurt M, Ozderin YO, Kurt OK
Pathol Res Pract. 2011 Jun 15; 207(6):359-65.
Hepatic granulomas are due to cell-mediated immunological responses to TB antigens and consist of
focal aggregates of macrophages, including Kupffer cells that may coalesce to form Langerhans giant
cells with surrounding lymphocytes and fibroblasts---- Hepatic granulomas: a clinicopathologic analysis of
86 cases.Turhan N, Kurt M, Ozderin YO, Kurt OK Pathol Res Pract. 2011 Jun 15; 207(6):359-65./ Hepatic
granulomas: a clinicopathologic analysis of 86 cases. Turhan N, Kurt M, Ozderin YO, Kurt OK Pathol Res
Pract. 2011 Jun 15; 207(6):359-65. Hepatic granulomas in response to TB tend to be necrotizing with
central caseation [----Hepatic granulomas: a clinicopathologic analysis of 86 cases.Turhan N, Kurt M,
Ozderin YO, Kurt OK Pathol Res Pract. 2011 Jun 15; 207(6):359-65.

Hepatic TB patients often had an inverted albumin to globulin ratio (A/G), in which the serum globulin
was reported to be 1.25-1.86 times higher than serum albumin----- Desai CS, Joshi AG, Abraham P,
Desai DC, Deshpande RB, Bhaduri A, et al. Hepatic tuberculosis in absence of disseminated abdominal
tuberculosis. Ann Hepatol. 2006;5:41–43

A high index of clinical suspicion is required to make a diagnosis of hepatic TB. In TB-endemic regions,
hepatic TB should be considered in patients who present with any combination of chronic right upper
quadrant pain, hepatomegaly, fever, and weight loss [51]. An infiltrative pattern on liver function test
with elevated ALP and GGT, as well as an inverted albumin/globulin ratio, would further support a
clinical diagnosis of hepatic TB----Hepatic tuberculosis: comparison of miliary and local form.Chien RN,
Lin PY, Liaw YF Infection. 1995 Jan-Feb; 23(1):5-8.-------- Hwang SW, Kim YJ, Cho EJ, Choi JK, Kim SH,
Yoon JH, et al. Clinical features of hepatic tuberculosis in biopsy-proven cases. Korean J Hepatol.  2009;
15:159–167. doi: 10.3350/kjhep.2009.15.2.159.

Plain x-ray radiography and ultrasound are generally the most widely available and first imaging tests to
be obtained, but they both lack diagnostic specificity--- Hepatic tuberculosis mimicking Klatskin tumor:
a diagnostic dilemma.Arora R, Sharma A, Bhowate P, Bansal VK, Guleria S, Dinda AKIndian J Pathol
Microbiol. 2008 Jul-Sep; 51(3):382-5. ----- Macronodular hepatic tuberculosis necessitating hepatic
resection: a diagnostic conundrum. Vimalraj V, Jyotibasu D, Rajendran S, Ravichandran P, Jeswanth S,
Balachandar TG, Kannan DG, Surendran R Can J Surg. 2007 Oct 10; 50(5):E7-8.

Ultrasound has the benefit of being easily operated in TB-endemic resource-limited settings [53]. The
median proportion of patients with abnormal abdominal ultrasound was 76% (range: 6-100%) among
hepatic TB case series. However, abdominal ultrasound generally showed a round, non-specific
hypoechoic region in the liver, and is therefore not an optimal test for hepatic TB---- Primary
macronodular hepatic tuberculosis: US and CT appearances.Levine C Gastrointest Radiol. 1990 Fall;
15(4):307-9.//// The nodular form of hepatic tuberculosis: contrast-enhanced ultrasonographic findings
with pathologic correlation. Cao BS, Li XL, Li N, Wang ZY J Ultrasound Med. 2010 Jun; 29(6):881-8.

Echogenic lesions of hepatic TB have also been described--- Ultrasound findings in hepatic mycobacterial
infections in patients with acquired immune deficiency syndrome (AIDS).Wetton CW, McCarty M,
Tomlinson D, Rosbotham J, Crofton ME Clin Radiol. 1993 Jan; 47(1):36-8.
The primary value of plain radiographs or ultrasound would be to prompt further investigation and/or
identify correct location for percutaneous liver biopsy-----4 studies from 1984 ---2008

The optimal radiographic test for diagnosing hepatic TB is a contrast-enhanced abdominal CT scan or a
dedicated triple-phase liver CT scan. The median proportion of patients with abnormal abdominal CT
was 88% (range: 40-100%) among hepatic TB case series (Table 4). The CT findings are different for
miliary and local hepatic TB. Miliary hepatic TB, which has smaller tubercles, is visualized on a CT scan as
multiple, low-density micronodules dispersed throughout the liver [60]. CT imaging for miliary hepatic
TB may also reveal hepatomegaly without nodular intrahepatic lesions, or it may reveal abdominal
lymphadenopathy with peripheral lymph node enhancement and/or calcifications [59-61]. By contrast,
local hepatic TB generally appears on CT as one large solitary nodule or 2–3 low-density nodules 

Liver biopsy with mycobacterial culture is considered the most specific diagnostic test for hepatic TB---
Hepatobiliary tuberculosis.Alvarez SZ J Gastroenterol Hepatol. 1998 Aug;// Essop AR, Posen JA,
Hodkinson JH, Segal I. Tuberculosis hepatitis: a clinical review of 96 cases. QJM.  198

Conclusion: Abdominal radiography and ultrasound are non-specific imaging modalities, and a CT scan
can be more accurate and should be preferred if available. Liver biopsy with mycobacterial culture and
histology is the most specific test for diagnosing hepatic TB, but has poor sensitivity (or a high false
negative rate). PCR of biopsy specimens has demonstrated high sensitivity and specificity for diagnosing
hepatic TB. Patients with definitive or clinically suggestive hepatic TB should be promptly initiated on 4-
drug anti-TB therapy, and clinicians should observe closely for drug toxicity and complications, such as
DILI and TB-IRIS. Co-infection with HIV can complicate the management of hepatic TB, and clinicians
must be knowledgeable of differences in pathophysiology, treatment, and disease management. A high
index of suspicion for hepatic TB is important if clinicians are to make an early diagnosis and initiate
prompt treatment to improve clinical outcomes.--- Hickey, A. J., Gounder, L., Moosa, M. Y., & Drain, P.
K. (2015). A systematic review of hepatic tuberculosis with considerations in human immunodeficiency
virus co-infection. BMC infectious diseases, 15, 209. https://doi.org/10.1186/s12879-015-0944-6

Hickey, A. J., Gounder, L., Moosa, M. Y., & Drain, P. K. (2015). A systematic review of hepatic
tuberculosis with considerations in human immunodeficiency virus co-infection. BMC infectious
diseases, 15, 209. https://doi.org/10.1186/s12879-015-0944-6

Table 5
Traditional and updated diagnostic criteria for hepatic TB

Diagnostic criteria in 1984 [ 18 ] Updated diagnostic criteria in 2014*

• Acid fast bacilli on smear of liver tissue • Culture of liver tissue demonstrating M. tuberculosis
 Diagnostic criteria in 1984 [ 18 ] Updated diagnostic criteria in 2014*

• Culture of liver tissue demonstrating M. • Acid fast bacilli on smear or nucleic acid (PCR) positive for TB
tuberculosis (IS6110 insertion sequence) from liver tissue sample

• Caseating hepatic granulomata with a • Abdominal CT demonstrating low-density hepatic nodule(s)

positive Mantoux reaction (<2 mm: miliary; >2 mm: local) in patient with confirmed pulmonary
TB or in a TB-endemic region

• Hepatic granulomata with • Clinical presentation of right upper quadrant pain, hepatomegaly,
demonstration of TB bacilli anywhere fever, and weight loss in patient with confirmed pulmonary TB or in
else in the patient a TB-endemic region**

• Typical appearance at laparotomy • Resolution of elevated liver enzymes following anti-TB therapy

• Autopsy confirmation of hepatic TB

• Response to specific therapy

TB = Tuberculosis; PCR = Polymerase chain reaction; CT = Computed tomography.

*Diagnostic criteria are presented from the strongest evidence to the weakest evidence.
**When available, other diagnostic tools such as radiography and liver biopsy should be employed to confirm
clinical diagnosis.
Hepatobiliary tuberculosis most commonly affects people in the 11– to 50-year-old age group with the
peak incidence of the disease reported in the second decade of life [11]. The disease has a 2:1 male
preponderance. Isolated hepatic tuberculosis is however more common in the fourth to sixth decades of
life

Lymphadenitis is the most commonly occurring form of extrapulmonary tuberculosis. Cervical

adenopathy is most common, but inguinal, axillary, mesenteric, mediastinal, and intramammary
involvement all have been described. -- Golden MP, Vikram HR. Extrapulmonary tuberculosis: an
overview. Am Fam Physician. 2005 Nov 1;72(9):1761-8. PMID: 16300038.

Males appear to be more frequently affected by miliary TB in pediatric as well as adult series.21–38--
Ray, S., Talukdar, A., Kundu, S., Khanra, D., & Sonthalia, N. (2013). Diagnosis and management of
miliary tuberculosis: current state and future perspectives. Therapeutics and clinical risk management, 9,
9–26. https://doi.org/10.2147/TCRM.S29179 (Retraction published Ther Clin Risk Manag. 2015 Sep
28;11:1457)

TB occurs in all countries and age groups, with 90% of infections being reported in
adults (aged ≥15 years).--- WHO--- Muneer, A., Macrae, B., Krishnamoorthy, S. et
al. Urogenital tuberculosis — epidemiology, pathogenesis and clinical features. Nat Rev
Urol 16, 573–598 (2019). https://doi.org/10.1038/s41585-019-0228-9

The central event in the development of miliary TB is a massive lymphohematogenous dissemination

of M. tuberculosis from a pulmonary or extrapulmonary focus and embolization to the vascular beds of
various organs. It most commonly involves the liver, spleen, bone marrow, lungs, and meninges.--- Ray,
S., Talukdar, A., Kundu, S., Khanra, D., & Sonthalia, N. (2013). Diagnosis and management of miliary
tuberculosis: current state and future perspectives. Therapeutics and clinical risk management, 9, 9–26.
https://doi.org/10.2147/TCRM.S29179 (Retraction published Ther Clin Risk Manag. 2015 Sep
28;11:1457)

Of the 10 million annual incidences of TB, between 5% and 45% have features of
extrapulmonary TB (EPTB)5,6,7 affecting all organs of the body. Common sites of EPTB
are lymph nodes, pleura, bones, meninges and the urogenital tract. --- Muneer, A.,
Macrae, B., Krishnamoorthy, S. et al. Urogenital tuberculosis — epidemiology, pathogenesis and
clinical features. Nat Rev Urol 16, 573–598 (2019). https://doi.org/10.1038/s41585-019-0228-9

TB is caused by bacilli of the Mycobacterium tuberculosis complex (MTBC)5,6,27,28,29.

These bacilli include Mycobacterium tuberculosis (Mtb), Mycobacterium
bovis, Mycobacterium africanum (which causes human TB in West and East
Africa), Mycobacterium caprae, Mycobacterium pinnipedii, Mycobacterium
microti and bacillus Calmette–Guérin (BCG), the derivative of M. bovis used in
vaccines. Mtb and M. africanum are the most frequent causes of human TB causing
an estimated 98% of infections. M. bovis is the next most common cause of TB and is
responsible for an estimated 1.8% of cases3---- Muneer, A., Macrae, B., Krishnamoorthy, S. et
al. Urogenital tuberculosis — epidemiology, pathogenesis and clinical features. Nat Rev
Urol 16, 573–598 (2019). https://doi.org/10.1038/s41585-019-0228-9

Intermittent dissemination of tubercle bacilli may lead to a prolonged fever of unknown origin
(FUO).---- https://www.msdmanuals.com/professional/infectious-
diseases/mycobacteria/extrapulmonary-tuberculosis-tb

Risk factors for developing TB include malnutrition, HIV infection, diabetes, chronic
renal and liver disease…., --- Muneer, A., Macrae, B., Krishnamoorthy, S. et al. Urogenital
tuberculosis — epidemiology, pathogenesis and clinical features. Nat Rev Urol 16, 573–598
(2019). https://doi.org/10.1038/s41585-019-0228-9

Disseminated tuberculosis (TB) is defined as having two or more noncontiguous sites resulting from
lymphohematogenous dissemination of Mycobacterium tuberculosis.1 Extrapulmonary involvement
occurs in one-fifth of all TB cases2 and it may occur in the absence of histological and radiological
evidence of pulmonary infection.--- Ribeiro, S., Trabulo, D., Cardoso, C., Oliveira, A., & Cremers, I.
(2015). Disseminated Tuberculosis in an Immunocompetent Patient: The Answer is in the Liver. GE
Portuguese journal of gastroenterology, 23(4), 208–213. https://doi.org/10.1016/j.jpge.2015.10.002

Extrapulmonary sites of infection commonly include lymph nodes, pleura, and osteoarticular
areas, although any organ can be involved. ---- Golden MP, Vikram HR. Extrapulmonary
tuberculosis: an overview. Am Fam Physician. 2005 Nov 1;72(9):1761-8. PMID: 16300038.

In small nodular hepatic lesions that are below the resolution of US or CT, the only imaging finding is
hepatomegaly. US may demonstrate tiny hypoechoic lesions with a “bright liver pattern”. ---- ROLE OF
ULTRASOUND IN THE DIAGNOSIS OF EXTRAPULMONARY TB: AN OVERVIEW--- Anna Lyn Corneja -
Egwolf, Chhaya Suresh, and Ma. Rosella Espinar St. Luke’s Medical Center, Philippines---
https://www.wfpiweb.org/Portals/7/Outreach/TB-Corner-Role-of-Ultrasound-in-the-Diagnosis-of-
Extrapulmonary-TB-May2016.pdf
congestive heart failure or due to liver cirrhosis with ascites, is considered to be a cause of
hypokalaemia because of inappropriate kaliuresis