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4 Metabolic disorders

usually good, although in more severe cases birthweight is
Table 14.4 Acute viral hepatitis in pregnancy reduced. Fetal death is common if the mother develops
Wernicke encephalopathy.11
Risk factors Physical features Laboratory tests
Vomiting may lead to dehydration, ketosis, weight loss, and
Intravenous No findings of chronic Blood picture
reflux esophagitis. Biochemical abnormalities include hypo-
drug use liver disease
chloremic alkalosis, electrolyte disturbance (severe hyponatre-
Sexual contact Tender hepatomegaly Coagulation tests
mia and hypokalemia) and mild hyperthyroidism (from elevated
Contact with Jaundice s. albumin,
human chorionic gonadotrophin [HCG]). Abnormal liver func-
infected persons s. bilirubin
tion, usually consisting of mild serum transaminases elevation,
Travel to countries Skin lesions with s. ALP
occurs in almost 50% of women with HG. The etiology and
where hepatitis HBV & HSV s. ALT/AST
mechanism of liver disease in HG is uncertain, but it may be
is endemic Subclinical (HCV) HAV IgM
related to impaired fatty acid oxidation.12 Synthetic liver function
Body piercing HBVsAg
remains normal and abnormalities reverse with treatment.
Blood transfusion HBVeAg
Hyperemesis often leads to hospitalization (and sometimes
(extremely rare) HBVcAb
multiple admissions) and may cause a psychological disturbance.
Drug-induced HCVAb
Rarely, repeated vomiting leads to esophageal rupture, pneumo-
hepatitis mimics HEV Ab
mediastinum, renal failure, or death from aspiration or Wernicke
encephalopathy from thiamine deficiency.13,14
Hospitalization is necessary for intravenous fluid replacement,
ALP ¼ alkaline phosphatase; ALT ¼ alanine aminotransferase;
monitoring, antiemetic therapy, psychological therapy, and,
AST ¼ aspartate aminotransferase; HAV ¼ hepatitis A virus;
occasionally, parenteral or enteral nutrition. Fluid and electrolyte
HBV ¼ hepatitis B virus; HCV ¼ hepatitis C virus; HEV ¼ hepatitis E virus;
abnormalities must be corrected. Hyponatremia is common and
HSV ¼ herpes simplex virus; CMV ¼ cytomegalovirus; EBV ¼ Epstein Barr
sodium-containing crystalloid fluids, with or without potassium,
virus; sAg ¼ surface antigen; eAg ¼ envelope antigen; cAb ¼ core
should be given cautiously, avoiding rapid correction and the
antibody; Ab ¼ antibody; IgM ¼ immunoglobulin M; s. ¼ serum
risk of central pontine myelinosis. Intravenous dextrose and car-
bohydrate loading should be avoided and thiamine and other
vitamin deficiencies, especially of the B group, corrected. Safe
same in pregnant and nonpregnant women), occurs more in late
antiemetic drugs include metoclopramide, droperidol, antihista-
pregnancy and with HEV infection, and is associated with a poor
mines, and 5-hydroxytryptamine-3 receptor antagonists.
prognosis. The incidence of preterm labor, fetal demise, and
Histamine receptor blockers or proton pump inhibitors may be
neonatal asphyxia is higher in patients with fulminant hepatitis.
useful in preventing esophagitis. Iatrogenic complications result
Hepatic encephalopathy and hepatorenal syndrome have a
from central venous catheterization, parenteral nutrition, or drug
higher incidence during pregnancy.
In the absence of advanced disease, infectious complications
during pregnancy are often minor.
If anesthesia is required it is important to remember that
Intrahepatic cholestasis of pregnancy
halothane and sevoflurane have been associated with fulminant
liver failure8 and severe acute hepatitis.9 Ketamine may have hepa- Intrahepatic cholestasis of pregnancy (IHCP) (see Table 14.5) is
the second most frequent cause of cholestasis and jaundice dur-
toprotective effects mediated through a reduction in cyclooxygen-
ing pregnancy, after viral hepatitis. The prevalence is <1 in 1000
ase-2 (COX-2) and inducible nitric oxide synthase (iNOS) protein.
(0.1%), but in Scandinavia and Chile it reaches 2“25% in certain
In the absence of shock or coagulopathy, regional anesthetic tech-
populations. Many cases are subclinical1 and recurrence in sub-
niques are suitable; however, it has been shown that general
sequent pregnancies is common. Intrahepatic cholestasis of
anesthesia does not affect survival in patients with advanced liver
disease.10 pregnancy is a genetic disorder predisposing a woman to
increased cholestasis during pregnancy or while taking oral con-
traceptives.15 Among women who develop jaundice on oral con-
Hyperemesis gravidarum
traceptives 50% have had IHCP in a prior pregnancy, and IHCP is
more common with advanced maternal age and multiparity.1,4
Most women experience nausea and vomiting in early pregnancy,
Most cases occur in the second half of pregnancy, although IHCP
which usually resolves by 12“16 weeks™ gestation. Hyperemesis
can occur as early as 6 weeks.4 Intrahepatic cholestasis may be
gravidarum (HG) is protracted nausea and vomiting of sufficient
due to dysfunction of bile secretion by active hepatocellular
severity that adequate hydration and nutrition are not main-
transporters,16 resulting in intracellular accumulation of toxic
tained. Risk factors include nulliparity, younger age, high satu-
bile acids causing liver cell injury. Liver biopsy shows dilated
rated fat intake and obesity, female fetus, twins, and hydatidiform
bile canaliculi, minimal inflammatory response, and nonspecific
mole. The incidence is 0.5“10 per 1000 pregnancies and the con-
dition may recur in a subsequent pregnancy. Fetal outcome is

Chapter 14

Obstetric implications
Table 14.5 Intrahepatic cholestasis of pregnancy (IHCP)
Intrahepatic cholestasis of pregnancy poses few maternal problems,
but there is poor fetal prognosis from transfer of bile acids from
Clinical features
mother to fetus (bilirubin does not cross the placenta significantly).
onset third trimester, sometimes second
Accumulation of bile acids in the cord blood serum, meconium, and
pruritus prominent
amniotic fluid may account for diminished fetal well-being and
jaundice mild
sudden intrauterine death in IHCP. More severe cases are asso-
no anorexia, malaise, or
ciated with low birth weight and prematurity,19 but perinatal
mortality does not differ from that of the general population. In
genetic disposition
women with IHCP, ursodeoxycholic acid (UDCA) therapy and
recurrence common
close maternal“fetal surveillance is indicated. Delivery should
Laboratory changes
occur near term following confirmation of fetal lung maturity, or
s. bile acids 10“100 fold increase
earlier if the fetus is compromised. Ursodeoxycholic acid is a
s. ALP 7“10 fold increase
hydrophilic bile acid that displaces toxic bile acids from hepatic
s. ALT/AST 2“10 fold increases
membranes, reducing the toxic bile acid content in both mother
s. GGT normal
and fetus.20 Ursodeoxycholic acid also lowers the amount of bile
s. bilirubin normal or slight increase
acids present in colostrum. Ursodeoxycholic acid is safe and more
s. cholesterol 2“4 fold increase
effective than cholestyramine and has replaced it in the treatment
s. triglycerides normal to slight increase
of IHCP.20 Ursodeoxycholic acid is especially useful in severe
prothrombin time normal to 2 fold increase
forms of IHCP, or when there is a history of sudden fetal death in
Differential diagnosis
a previous pregnancy.21 In one series,22 twelve pregnancies were
viral hepatitis
managed expectantly and there were eight stillbirths and two pre-
mature deliveries (fetal distress with one death, one C/S for fetal
autoimmune disorders
distress). Subsequently, these investigators treated three women
sclerosing cholangitis
who had IHCP with UDCA. No perinatal morbidity or mortality
primary biliary cirrhosis
occurred. Intrahepatic cholestasis of pregnancy starts to resolve
extrahepatic cholestasis
spontaneously within 24 hours of delivery, although jaundice and
drug toxicity
abnormal liver function tests may persist for months. If symptoms
Dubin-Johnson syndrome
of liver disease persist beyond this time then chronic hepatopathy
ALP ¼ alkaline phosphatase; AST ¼ aspartate aminotransferase; must be ruled out.
ALT ¼ alanine aminotransferase; GGT ¼ g-glutamyl-transpeptidase;
s. ¼ serum Management and anesthetic implications
Concerns for the anesthesiologist in IHCP include the degree of
hepatic disease and the possibility of planned near-term obstetric
Common symptoms include malaise, abdominal discomfort, interventions (e.g. early induction of labor). Decreased small
subclinical steatorrhea, and pruritus. Abdominal pain warrants intestinal bile acid concentrations can lead to impaired absorp-
investigation for viral hepatitis or cholelithiasis (see Table 14.5). tion of fats and fat-soluble vitamins, resulting in steatorrhea and
deficiencies in vitamins A, D, E, and K.23 Although unusual, coa-
Pruritus results from reduction in bile flow, and reduced bile and
bile salt excretion, and typically starts in the extremities (palms and gulopathy may occur with IHCP and a case of epidural hematoma
complicating cholestasis of pregnancy has been reported.24
soles) before extending to the trunk and face. Although elevation of
plasma bile salts is associated with itching, there is no correlation Injection of vitamin K and fresh frozen plasma can prevent coag-
between the concentration of bile salts and severity of the itch. ulopathy. If cholestyramine is used, prophylactic vitamin K
Itching is often severe, disrupts sleep at night, responds poorly to should be given. There is an increased risk of postpartum hemor-
treatment and, after one to two weeks, mild jaundice appears in 50% rhage (PPH) so the patient should have blood crossmatched and
of cases. Other causes of pruritus should be ruled out, including large-bore intravenous lines inserted.
thyroid disease, renal failure, lymphoma, anemia, and drug reac- Ondansetron may be effective treatment for IHCP-associated
pruritus.25 Opioids, especially neuraxial opioids, may exacerbate
tions. Physical examination is usually normal in IHCP, but skin
excoriation from scratching may be seen. The earliest biochemical the pruritus, but effective pain management should be used.
changes are a 10“100 times increase in serum bile acids. The mea-
surement of glutathione S-transferase alpha (GSTA), a specific mar-
Acute fatty liver of pregnancy
ker of hepatocellular integrity, distinguishes women with IHCP from
those with benign pruritus gravidarum.18 Serum bilirubin is typi- Acute fatty liver of pregnancy (AFLP) is a rare and potentially fatal
disorder with an incidence of 1 in 7“15 000 pregnancies.26,27 It
cally elevated. Although transaminases may increase as much as
two- to ten-fold (up to 1000 U/l) in 60% of cases, moderate to severe presents in the third trimester, often close to term, although it can
occur earlier.28 Acute fatty liver of pregnancy affects all ages, races,
elevations suggest the possibility of other hepatic disease such as
drug-induced or viral hepatitis. Gamma-GT is usually normal. and ethnicities, and may appear after several normal pregnancies.

4 Metabolic disorders

Acute fatty liver of pregnancy is most common in twin, nulliparous,
Table 14.6 Acute fatty liver of pregnancy (AFLP)
and male-fetus pregnancies29 and recurrence in a subsequent preg-
nancy is unusual.30 Early diagnosis may be difficult, since 40% of Clinical features
cases have preeclampsia, and 20% have hemolysis, elevated liver Onset second half of pregnancy
enzymes, and low platelets (HELLP) syndrome.30,31 Greater aware- Nausea, vomiting, malaise, and jaundice prominent
ness, intensive therapy, and prompt delivery of the fetus have Hypoglycemia prominent
resulted in a significant reduction in maternal mortality.27,32 Preeclampsia often coexists (features are hypertension,
Metabolic, synthetic, and excretory functions of the liver are proteinuria, right upper-quadrant pain)
abnormal due to fat infiltration and inflammation.1,2,3,4,5,6,30 Acute Abdominal pain
fatty liver of pregnancy occurs in 30“80% of pregnancies in which Less common presentations
the fetus has a long-chain 3-hydroxyacyl-CoA dehydrogenase Headache
(LCHAD) deficiency. Long-chain 3-hydroxacyl-CoA dehydrogenase Backache
is one of four enzymes that are part of a trifunctional protein Hematemesis
complex on the inner mitochondrial membrane, responsible for Necrotizing enterocolitis
long-chain fatty acid metabolism in the liver. When the infant of a Fulminant acute liver failure (severe hypoglycemia,
heterozygous woman is homozygous or even heterozygous for one renal failure, lactic acidosis, gastrointestinal
of these mutations, it is unable to oxidize 3-hydroxy fatty acids, and bleeding, and impaired consciousness or
may present in infancy or after extended fasting with a Reye-like encephalopathy)
syndrome.1,2,3,4,6,33 During pregnancy, excess fetal fatty acids trans- Laboratory changes
fer to the mother and accumulate in her liver. Acute fatty liver of s. bilirubin normal or slight increase
pregnancy may also be associated with deficiencies in carnitine s. ALT/AST increase to 1000 U/l
palmitoyltransferase I, and medium- and short-chain acyl-CoA s. GGT slight increase
dehydrogenase.34 Serum bilirubin and aminotransferases are s. fibrinogen low
usually moderately elevated and serum AST levels are $300U/l prothrombin time high
(up to 1000U/l). Hypoglycemia can result from depression of blood glucose low
glucose-6-phosphatase activity and is often profound. Marked neu- s. uric acid increased
trophil leukocytosis to 30 000/mm3, with left shift, and microangio- s. ammonia increased
pathic hemolytic anemia with thrombocytopenia are frequently platelet count normal or low
present. Disseminated intravascular coagulation with elevated
AST ¼ aspartate aminotransferase; ALT ¼ alanine aminotransferase;
fibrin degradation products and low fibrinogen are less common.
GGT ¼ g-glutamyl-transpeptidase; s. ¼ serum
Oliguria may be accompanied by abnormalities of serum electro-
lytes and of urine biochemistry. Elevated serum creatinine and
ammonia levels occur, even in early disease, and metabolic acidosis
results from high serum lactate levels.1,2,3,4,6,30 reveal other liver or biliary tract abnormalities. Diagnostic liver
biopsy is often precluded by the bleeding risk.1,2,3,4,5,30
Clinical features
Management and obstetric implications
The symptoms of AFLP develop over one to seven days and include
malaise, nausea and vomiting, abdominal pain, fever, and jaun- Appropriate supportive therapy is based on invasive monitoring,
dice, although there are a variety of less frequent features (see and correction of hypoglycemia and coagulopathy. About 50%
Table 14.6). Jaundice is more common with viral hepatitis, choles- of cases have coagulopathic bleeding, requiring transfusion of
tasis, bile duct obstruction, or preeclampsia. Pruritus is uncom- blood products; this may worsen postpartum when antithrombin
levels fall further.30 Gastrointestinal hemorrhage, sepsis, pan-
mon (incidence 5“30%), tachycardia is common, and the liver size
is normal.1,2,3,4,5,30 Other complications include renal failure, acute creatitis, or diabetes insipidus may also require treatment. In
respiratory distress, and diabetes insipidus. Pancreatitis, with those with preeclampsia, adjustment of the dose of magnesium
pseudocyst formation and retroperitoneal bleeding, may occur in is necessary when renal impairment is present. Patients who
those with severe disease and is detected by imaging studies, and develop encephalopathy may require intubation and ventilation.
an elevated serum lipase, or, less frequently, amylase.35 After resuscitation and stabilization, expeditious delivery is essen-
Although AFLP can be confused with severe preeclampsia, tial and improvement in liver function invariably follows, which
improves maternal prognosis.27,31 Fetal and neonatal abnormalities
distinguishing features are hypoglycemia, hyperammonemia,
and less chance of right upper quadrant (RUQ) pain or hyperten- include prematurity, intrauterine growth restriction, intrapartum
sion. The diagnosis is based on typical clinical and biochemical hypoxia, and hypoglycemia. Neonates with LCHAD deficiency can
findings (mildly elevated aminotransferases between 100 and experience failure to thrive, hepatic failure, cardiomyopathy, hypo-
glycemia, and death.32,33 In the postpartum period maternal recov-
1000 U/l, mildly elevated bilirubin, and increased ammonia).
Other differential diagnoses include cholestasis and viral hepati- ery is rapid, starting with normalization of prothrombin time
tis. Ultrasonographic or computed tomographic (CT) imaging to followed by a return to normal of all liver function tests within four
detect liver fat accumulation is not always positive, but may weeks. Nevertheless, intensive care is still required for several days

Chapter 14

postpartum because of the risk of maternal hypoglycemia. Genetic Portal hypertension may occur in the absence of cirrhosis from
counseling should be offered about future risk of recurrence. portal vein thrombosis or congenital hepatic fibrosis. In preg-
nancy, the diversion of blood through the azygous venous system
Anesthetic implications and reflux esophagitis further predispose to variceal bleeding.
The anesthesiologist should assist with optimization of medical Sixty percent of women with varices suffer hematemesis, espe-
cially during late pregnancy47,48 and this is associated with a 30%
therapy by initiating invasive monitoring. Blood pressure (BP),
mortality rate.46,47 Therapy includes beta-blockade to lower por-
blood glucose, fluid balance, electrolytes, coagulation, and acid“
base status need regular assessment. Arterial cannulation is valuable tal pressure, sclerotherapy, and banding, but if these fail surgical
intervention such as spleno-renal shunt may be required.49
and good venous access via a central venous or peripherally inserted
central catheter assists with infusion of dextrose and parenteral Women with existing shunts are at a lower risk of hematemesis
and the outcome of pregnancy is usually good.1 Fifty percent of
nutrition, correction of low serum calcium and hypovolemia, main-
tenance of adequate urinary output, and treatment of hypertension. patients with cirrhosis and significant portal hypertension
Prophylactic administration of an H2-receptor antagonist is war- develop a complication such as anemia from chronic illness or
ranted to reduce the risk of gastric erosion, ulceration, and esopha- bleeding varices, and thrombocytopenia as a result of hyper-
gitis. Coagulopathy is common so administer vitamin K with blood splenism. Rupture of a splenic artery aneurysm occurs in approxi-
products reserved for a bleeding diathesis. Successful liver trans- mately 2% and is associated with very high maternal and fetal
plant has been reported,36,37 the primary indications being raised mortality.3
intracranial pressure or deterioration of neurologic function.
Obstetric and anesthetic implications
There are few reports describing the anesthetic management of
patients with AFLP. Uneventful epidural anesthesia, which pre- Deterioration of hepatic function during pregnancy is precipitated
serves hepatic blood flow, has been described;38 however, in all by bleeding, sepsis, hypotension, or drugs, including analgesics.
but mild cases, coagulopathy contraindicates regional anesthe- Drugs with antiplatelet activity potentiate the bleeding risk.
sia. Consequently, general anesthesia usually is required for Impaired acetaminophen and morphine-3 and 6-glucuronide
C/S.39,40,41 In such cases, or if severe thrombocytopenia is pre- metabolism may produce hepatic toxicity and central nervous sys-
sent, intramuscular injections, acetylsalicylic acid, and nonster- tem depression respectively, so opioids without active metabolites,
oidal anti-inflammatory drugs (NSAIDs) should be avoided. If such as fentanyl, are preferable. Intra-abdominal surgery on
regional block is suitable, an argument can be made for spinal patients with advanced cirrhosis is associated with high 30-day
anesthesia, because of the smaller needle and lower risk of vas- mortality (60% or more), especially if emergency surgery is required
or the patient is significantly coagulopathic.50 Spontaneous abor-
cular bleeding. If epidural anesthesia is used it is advisable to
tion and neonatal mortality rates are increased.47,51
remove the epidural catheter immediately after delivery.
Aims of general anesthesia are to maintain liver and renal blood The presence of midline varices and caput medusa may favor a
vaginal delivery rather than C/S.52 If vaginal delivery is planned
flow and avoid hepatotoxicity. As propofol has normal pharmaco-
kinetics in cirrhosis and does not alter hepatic blood flow it may be and coagulation is normal, epidural or spinal analgesia will pre-
the best induction agent.42,43 Desflurane has negligible hepatic meta- vent straining during delivery.53 If general anesthesia is required,
bolism44 while prolonged administration of isoflurane causes mild the principles of anesthesia that pertain to acute liver failure (see
derangement of hepatocellular function in healthy individuals.44 below) are applicable.
Nitrous oxide should be avoided. Succinylcholine is not contra-
indicated, but may cause prolonged neuromuscular block due to a
Liver tumors
low plasma cholinesterase. Atracurium is the preferred nondepolari-
zing neuromuscular blocking drug. Rocuronium shows great indivi- Pregnancy complicated by hepatocellular carcinoma, cholangio-
dual variability among patients with hepatic impairment.45 In the carcinoma, hepatic adenoma, and focal nodular hyperplasia (a
presence of fulminant hepatic failure, exaggerated responses to vascular benign tumor) is very rare. Hepatocellular carcinoma is a
anesthetics and opioid analgesics may occur because of poor meta- very rare primary malignancy or more often, secondary to chronic
bolism and central depression associated with encephalopathy. hepatitis, especially HCV hepatitis. Benign hepatic adenomas
occur almost only in women, and oral contraceptives are impli-
cated in the pathogenesis. During pregnancy, estrogens may sti-
Cirrhosis and portal hypertension
mulate tumor growth, and hemorrhagic rupture into the tumor or
Cirrhosis is caused by a number of conditions, especially chronic abdominal cavity occurs in 25% of cases. This event is associated
with high maternal and fetal mortality.54,55 Termination of
hepatitis C, D, and E, or alcoholism, but is rare in women of child-
bearing age (incidence 1 in 2000).46 Pregnancy is less common in pregnancy is recommended, but successful resection of adeno-
advanced cirrhosis as altered metabolism of the sex steroids leads mas > 5 cm, or of carcinoma by partial hepatectomy in the second
trimester has been performed.56,57 Presence of cirrhosis and
to infertility, but improvements in care mean that women with well-
compensated cirrhosis may become pregnant. In approximately metastatic disease requires assessment and careful preoperative
25% of pregnant women with cirrhosis, liver function will deterior- planning. Intraoperative fetal monitoring is warranted if the fetus
ate47 and portal venous pressure will increase resulting in esopha- is viable. If resection is attempted, massive hemorrhage is
geal varices, ascites, and portal hypertensive encephalopathy. expected and cell salvage should be considered.

4 Metabolic disorders

Table 14.7 Features of hepatolenticular degeneration Table 14.8 Diseases associated with Budd-Chiari syndrome
(Wilson disease)
Polycythemia vera rubra
Usually asymptomatic until early adulthood Paroxysmal nocturnal hemoglobinuria
50% present with hepatic involvement Inherited thrombophilias
 acute and chronic hepatitis  antithrombin, protein C or S deficiency
 cirrhosis  factor V Leiden
 fulminant hepatitis with hemolytic anemia Malignancy

50% present with neurologic, psychiatric, or behavioral abnormalities
ceruloplasmin and clinical improvement or remission may occur.
 loss of fine hand movements
Discontinuing treatment may lead to relapse, presenting as a
severe hemolytic crisis (requiring blood transfusion and plasma
 loss of coordination
exchange) or fulminant liver failure,62 and the fetus may suffer liver
damage. Although penicillamine and trientine have a low risk of
congenital malformations, zinc is the preferred chelating agent.63
Genetic counseling should be offered.

Anesthetic implications
Hepatolenticular degeneration (Wilson disease)
There are very few case reports describing obstetric anesthesia in
women with Wilson disease.61 Anesthetic assessment should
Hepatolenticular degeneration or Wilson disease is an autosomal
recessive disorder, involving a gene on chromosome 13 that encodes include a review of psychological status and evaluation of hepatic
a copper-transporting ATPase. More than 20 gene mutations function, thrombocytopenia, coagulopathy, skin abnormalities,
account for variable clinical expression, resulting in reduced copper and neurological involvement. If esophageal varices are present,
excretion into bile, and inhibition of the plasma copper binding neuraxial analgesia and instrumental delivery will avoid straining
transport protein ceruloplasmin.2,54 The worldwide prevalence is 1 and possible variceal hemorrhage.53
in 20 000.58 Copper is an inorganic nutrient, essential to life, and is Neuromuscular blocking drugs should be used with caution and
monitored because of myasthenic syndrome,61 and careful atten-
present in cytochrome C oxidase, monoamine oxidase, and tyrosi-
nase. The accumulation of free and tissue copper damages the liver, tion to asepsis is required in the presence of bone marrow toxicity.
brain, and other organs, although not usually the kidney. Regional techniques are valuable, if not contraindicated, although
The diagnostic features of Wilson disease are liver disease and cranial nerve involvement may mandate general anesthesia. If
movement abnormalities (Table 14.7), although occasionally severe liver disease is present (see Acute liver failure), preparation
repeated spontaneous abortion or amenorrhea, or the presence for intra- and postpartum hemorrhage is advised.
of golden deposits of copper in Descemet™s membrane of the
cornea (Kaiser-Fleischer rings) leads to the diagnosis. The diag- Other liver diseases

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