-Primary hypothyroidism (non-autoimmune) is commonly observed in CKD patients.

Especially, the prevalence of subclinical hypothyroidism increases consistently

with decline in GFR.[52]
The earliest and the most common thyroid function abnormality in CKD patients is a
low T3 level (especially total T3 than free T3).[53] This “low T3 syndrome” occurs
in CKD due to several
reasons. Fasting, chronic metabolic acidosis and chronic protein malnutrition
affect iodothyronine deiodination, as well as protein binding of T3, reducing the
peripheral conversion of T4
to T3 and its protein binding. In addition, inflammatory cytokines such as tumor
necrosis factor (TNF)-a and interleukin (IL)-1 inhibit the expression of type 1 5’-
deiodinase, which is
responsible for peripheral conversion of T4 to T3.[54] In addition, impaired renal
handling of iodine increases serum iodine levels, causing a prolonged Wolff –
Chaikoff effect.[55]
The clinical importance of this low T3 syndrome is controversial. The low T3 levels
(especially total T3 and not free T3) in CKD patients have been correlated with
higher levels of
markers of inflammation [highly sensitive C-reactive protein (hsCRP), IL-6, etc.],
malnutrition (lower prealbumin, IGF-1), increased endothelial dysfunction, poorer
cardiac function,
poor survival, and higher all-cause as well as cardiovascular mortality in some
studies.[54,56] Some of these studies were underpowered to detect these
associations or did not exclude
confounders appropriately.[57] In some other studies, the low free T3 and not the
total T3 level is associated with increased mortality.[58] However, recent studies
have demonstrated
that this association is not invariable, and the free T3 levels may not be
associated with long-term mortality in CKD and dialysis patients.[59]

Subsequent studies also demonstrated a low T4 level in many CKD patients. However,
the free T4 levels vary from being low to normal in CKD. This is primarily because
of an impaired
protein binding of T4 in CKD. The thyroid profile is similar to that observed in
several non-thyroidal illnesses (NTIs) such as severe infections, heart failure,
malignancies, and in
several hospitalized patients without renal disease. This led to the consideration
of a “sick euthyroid state” in CKD, which is now called “non-thyroidal illness.”
However, unlike other
NTI states, there is no increase in total rT3 levels in CKD.[60] This is due to an
increased redistribution of rT3 into extravascular and intracellular spaces. In
some patients, due to
an impaired renal clearance, free rT3 levels may be mildly elevated. Another
difference from other NTIs is that the thyroid stimulating hormone (TSH) levels are
elevated in CKD. However,
TSH is released in response to thyrotropin releasing hormone (TRH) in CKD patients,
indicating pituitary disturbances in uremia.[61] In addition, the circadian rhythm
of TSH and its
glycosylation is altered in CKD, compromising its activity. Thus, CKD patients have
low T3 and normal or reduced T4 levels, and consequently elevated TSH and attendant
increase in
thyroid gland volume.[62–64] These mechanisms are probably reflective of the
physiological adaptation of the body to CKD to reduce the protein nitrogen
turnover, reduce the protein
catabolism and nitrogenous waste load.

-The present study evaluated thyroid hormone indices of patients with acute renal
failure without other systemic illnesses (n = 12), as compared to patients with
critical illnesses in
 the presence (n = 16) and absence (n = 6) of acute renal failure. Abnormalities in
the group with acute renal failure alone included decreased serum levels of total
T4 and T3, and
elevated levels of free rT3. Serum levels of free T4 by equilibrium dialysis and
the enzyme immunoassay, T3 uptake ratios, TSH and total rT3 were normal. These
findings are consistent
with the presence of decreased binding of T4 and rT3 to their serum carrier
proteins. Critically ill patients with acute renal failure differed in that they
had lower total T4 and T3
levels and elevated T3 uptake ratio values. As in the group with acute renal
failure alone, total rT3 levels were normal and free rT3 values were elevated. The
group with critical
illness alone differed only in that the total rT3 concentrations were elevated in
all patients. The alterations of thyroid hormone indices in acute renal failure are
similar to those
of other nonthyroidal illnesses with the exception of the normal total rT3 levels.
This suggests that the failing kidney or the metabolic consequences of uremia
specifically affect rT3
metabolism.

-They observed decreased total thyroid hormone and FT3 levels in 74% CKD patients
whereas TSH, FT4 were similar to controls.Our study found no significant
alterations in mean TSH level
in CKD patients as compared to controls. The mean TSH levels were comparable to
controls for the various ranges of GFR. TSH levels did not show any correlation
with the severity of renal
failure.] However, contrary to this, Joseph et al. demonstrated high TSH in the
presence of low thyroid hormones. They observed thyrotropin levels rising with
degree of renal
insufficiency, favoring a normal thyroid hypophyseal feedback loop.

-Moreover, impaired conversion of T4 and T3 may be related to malnutrition and

humoral factors including cytokines that are generally associated with CKD. [2] In
our study, serum total
T3 concentration was significantly lower than the normal range in the majority of
the CKD patients in comparison with the controls.Inhibitors of T4 binding to serum
carrier proteins
and urinary loss of TBG, albumin and pre-albumin contribute to the decreased levels
of the T4 in CKD patients. [2],[8] In our study, one-third of the CKD patients had
significantly lower
total serum T4 concentration than the controls.Serum TSH concentrations are usually
normal or elevated in CKD, but its response to its releasing hormone (TRH) is
generally low. [9] Both
proteinuria and GFR influence the activity of the pituitary-thyroid axis. [4],[6]
In our study, serum TSH concentration was significantly increased in 60% of the CKD
patients. Similar
findings were observed by previous studies. [4] In contrast, others found serum TSH
levels to be normal or unchanged in the CKD patients.

-Most patients with ESRD have decreased plasma levels of FT3, which reflect
diminished conversion of T4 to T3 in the periphery. [6],[10],[11] This abnormality
is not associated with
increased conversion of T4 to the metabolically inactive reverse T3 (rT3), because
plasma rT3 levels are typically normal.

-Rodrigues et al concluded that despite the fact that uremic patients on HD show
low serum levels of T3, changes in T3 influx and efflux in erythrocytes could act
as a compensatory
mechanism that neutralize thyroid hormone dysfunction in order to maintain the
euthyroid state. [17] In their study, Wiederkehr et al could find that correction
of metabolic acidosis
improves thyroid hormone axis in HD patients and may also lower morbidity and
mortality. [18] Although it is well known that use of erythropoietin leads to an
improvement of various
endocrine disorders, Resic et al concluded that patients on HD usually have
asymptomatic abnormalities of the thyroid gland, but the use of erythropoietin did
not improve their hormonal
status. [19] However, Utas et al concluded that recombinant human erythropoietin
therapy has some beneficial effects on the hypothalamo-pituitary-thyroid axis in
patients on regular HD.
[20]

-Hypothyroidism and renal impairment share some common features in between them
like symptoms of peri-orbital edema, generalized edema, gastrointestinal
manifestations of loss of
appetite; signs such as anemia, hypertension and pleural, pericardial effusions as
in our second case, so clinicians may err one to another. On contrary
hypothyroidism can also be
entirely asymptomatic as observed in our first case.