medical ideas

Primary hepatocellular carcinoma

Types of cirrhosis Alcoholic cirrhosis This is discussed in the section on alcoholic liver
Primary biliary cirrhosis Primary biliary cirrhosis (PBC) is a chronic disorder in which there is a progressive destruction of bile ducts, eventually leading to cirrhosis. Ninety per cent of those affected are women in the age range 40-50 years. It used to be rare but is now being diagnosed more frequently in its milder forms. The prevalence is approximately 7.5 per 100 000, with a marked increase in first-degree relatives. PBC has been called 'chronic non-suppurative destructive cholangitis'; this term is more descriptive of the early lesion and emphasizes that true cirrhosis occurs only in the later stages of the disease. more  in West

AETIOLOGY

The aetiology is unknown, but immunological mechanisms may play a part. Serum antimitochondrial antibodies are found in almost all patients with PBC, and of the mitochondria] proteins involved, the antigen M2 is specific to PBC. The finding of M4 and MS antigens in patients with M2 may be associated with more progressive disease. Five M2 specific antigens have been further defined using immunoblot techniques, of which the E2 component of the pyruvate dehydrogenase complex (PDC) is the major M2 autoantigen. The five antigens are a 72 kDa E2 subunit (PDC.E2), the 52 kDa protein X, the 50 kDa branched-chain 2-oxo-acid dehydrogenase complex (BCOADC.E2), the 48 klla 2-oxo-glutarate dehydrogenase complex (OGDC.E2), and the 41 lcDa El a-subunit of PDC. The presence of AMA in high titre is unrelated to the clinical or histological picture and its role in pathogenesis is unclear. It seems likely that an environmental factor acts on a genetically predisposed host. E. toll and other enterobacteria have been proposed as the triggering infective agent. Although damage to bile ducts is a feature, antibodies to bile ductules are not specific to PBC. Biliary epithelium from patients with PBC expresses aberrant class Il HLAs. but it is not known whether this expression is the cause or result of the inflammatory response. Cell-mediated immunity is impaired (demonstrated both in vitro and by skin testing), suggesting that sensitized T lymphocytes might be involved in producing damage. There may be a defect in immunoregulation, or a decrease in T suppressor cells which may allow cytotoxic T cells to


produce damage to the bile ducts. There is also-evidence to suggest that lymphokine secretion and cell activation by T lymphocytes is impaired at the site of tissue destruction. There is an increased synthesis of IgM, thought to be due to a failure of the switch from IgM to lgG antibody synthesi'.

CLINICAL FEATURES
 Asyminomahr patients are discovered on routine examination or screening to have hepatomegaly, a raised serum alkaline phosphatase or autoantibodies. Pruritus is often the earliest symptom, preceding jaundice by a few years. When jaundice appears, hepato-mcgaly is usually found. In the later stages, patients are jaundiced with severe pruritus. Pigmented xanthelasma on eyelids or other deposits of cholesterol in the creases of the hands may he seen. Hepatosplenomegaly is present.

ASSOCIATIONS
Autoimmune disorders (e.g. scleroderma, rheumatoid arthritis) occur with increased frequency. Keratoconjunctivitis sicca (dry eyes and mouth) is seen in 70% of cases. Renal tubular acidosis and membranous glomerulonephritis may occur.
SjOgren's syndrome,

INVESTIGATIONS

• Mitochondrial antibodies - measured routinely by ELISA (in tin-es >1:160) — are present in over 95% of patients. M2 antibody is specific. Other nonspecific antibodies (e.g. antinuclear factor and smooth muscle) may also he present
. • High serum alkaline phosphatase is often the only abnormality in the liver biochemistry.
 • Serum cholesterol is raised
. • Serum IgM may be very high
. • Ultrasound can show a diffuse alteration in liver architecture.
 • Liver biopsy shows characteristic histological features of a portal tract infiltrate mainly of lymphocytes and plasma cells; approximately 40% have granulomas. Most of the early changes are in zone 1. Later, there is damage to and loss of small bile ducts with ductular proliferation. Portal tract fibrosis and, eventually, cirrhosis is seen. Hepatic granulomas are not specific and are also seen in sarcoidosis, tuberculosis, schistosomiasis. drug reactions (e.g. phenylbutazone), brucellosis, parasitic infestation (e.g. strongvloidiasis) and other conditions.

DIFFERENTIAL DIAGNOSIS

The classical picture presents little difficulty with diag-nosis (high serum alkaline phosphatase and the presence of AMA); this can be confirmed by the characteristic features on liver biopsy. There is a group of patients with the histological changes of PBC, but the serology of autoimmune hepatitis (i.e. positive antinuclear and smooth muscle antibodies but negative AMA). This

 has been given the name of note cholanguis and responds to steroids and azathioprine. In the jaundiced patient, extrahepatic biliary obstruction should be excluded by ultrasound and, if there is doubt about the diagnosis, ERCP (or MRCP) should be performed to make sure that the bile ducts are normal.

TREATMENT

 Ursodeoxycholate (I0-15 mg kg 1..-1) is of benefit in some patients with improvement in serum liver enzymes and pruritus. and should be given to all patients. The results from all trials have shown a modest reduction in time to death or transplant. Corticosteroids and other immunosuppressive drugs have shown no clear benefit and are not now used. Malabsorption of fat-soluble vitamins (A, I-) and K) occurs and supplementation is required when deficiency is detected and in the jaundiced patient prophylactically. Calcium is required for osteoporosis. Hyperlipidaemia should be treated (see p. 994). Pruritus is difficult to control, but cholestyramine, one 4 g sachet three times daily, can be helpful, although it is unpalatable. Rifampicin and naloxone hydrochloride an opioid antagonist) have been shown to be of benefit in trials. The lack of effective medical therapy has nude PBC a major indication for orthotopic liver transplantation

COMPLICATIONS

 The complications are those of cirrhosis. In addition, osteoporosis, osteomalacia and a polyneuropathy can also occur.

COURSE AND PROGNOSIS

 This is very variable. Asymptomatic patients and those presenting with pruritus will survive for more than 20 years. Symptomatic patients with jaundice have a more rapidly progressive course and die of liver failure or bleeding varices in approximately 5 years. Liver transplantation should therefore be offered when the serum bilirubin reaches 100 Arno' L-1. Transplantation has a five-year survival of at least 70%.
Secondary biliary cirrhosis Cirrhosis can result from prolonged (for months) large duct biliary obstruction. Causes include bile duct strictures, gallstones and sclerosing cholangitis. An ultrasound examination, followed by ERCP or PTC, is performed to outline the ducts and any remedial cause is dealt with.
Hereditary haemochromatosis Hereditary haemochromatosis (HH) is an inherited disease characterized by excess iron deposition in various organs leading to eventual fibrosis and functional organ failure.

 PREVALENCE AND AETIOLOGY HH

 is transmitted by an autosomal recessive gene with a prevalence in caucasians of homozygotes (affected) of I in 400 and a heterozygote (carrier) frequency of 1 in 10. It is the most common single gene disorder in caucasians. It is associated with HLA-A3 (72% versus 28% of the general population); in addition HLA-B14 is increased in France and HLA-B7 in Australia. H14 has been shoWn to be due to a mutation in a gene initially designated HLA-H — now HFE — on the short arm of chromosome 6. Between 83% and 90% of patients with overt HH are homozygous for the Cys 282 Tyr mutation. A second mutation (His 63 Asp; C I 87G) occurs in about 25% of the population and is in complete linkage disequilibrium with Cys 282 Tyr. Dietary intakes of iron and chelating agents (ascorbic acid) are probably also important. Iron overload may be present in alcoholics, but alcohol excess per se does not cause HH. There is a history of excess alcohol intake in 25% of patients. Mechanism of damage. This is still unclear. The HFE gene may be involved in regulating the expression of other gene products including .the recently described divalent-cation transporter (DCTI) which may be a mediator in intestinal iron absorption. Iron is taken up by the mucosal cells inappropriately, exceeding the binding capacity of transferrin; excess iron is then taken up by the liver and other tissues gradually over a long period. It seems likely that it is the iron itself that precipitates fibrosis.
PATHOLOGY In symptomatic patients the total body iron content is 20-40 g, compared with 3-4 g in a normal person. The iron content is particularly increased in the liver and pancreas (50-100 times normal) but is also increased in all other organs (e.g. the endocrine glands, heart and skin). Gonadal function is impaired despite a low testicular iron content. In established cases the liver shows extensive iron deposition and fibrosis. Early in the disease, iron is deposited in the periportal hepatocytes (in pericanalicular lysosomes). Later it is distributed widely throughout all acinar zones, biliary duct epithelium, Kupffer cells and connective tissue. Cirrhosis is a late feature.

CUNICAL FEATURES

 The course of the disease depends on a number of factors, including sex, dietary iron intake, presence of associated hepatotoxins (especially alcohol) and genotype. Overt clinical manifestations occur more frequently in men; the reduced incidence in women is probably explained by physiological blood loss and a smaller dietary intake of iron. Most affected individuals present in the fifth decade. The classic triad of bronze skin pigmentation (due to melanin deposition), hepatomegaly and diabetes mellitus is only present in cases of gross iron overload.