Amyloidosis of the liver

No histopathological or organ weight changes were noted in the livers of male mice following daily dermal exposures for 1 week to 0.1 mL kerosene (Upreti et al. 1989). Slight hepatic karyomegaly was noted in mice exposed to 500-8,000 mg/kg/day JP-5 for 13 weeks (NTP/NIH 1986). Amyloidosis of the liver occurred in mice chronically exposed to 500 mg/kg/day JP-5 but not in those exposed to 250 mg/kg/day. 

Heterozygous carriers of functionally relevant mutations usually present with HDL cholesterol levels that are frequently below the fifth percentile. As would be expected, apoA-I levels are also frequently below the fifth percentile (i.e., < 1.05 g/1 and < 1.1 g/1 in Caucasian men and women, respectively). In most cases, heterozygous carriers of apoA-I variants do not present with specific clinical symptoms. An important exception are some structural apoA-I variants with amino acid substitutions in the amino terminus, which have been detected in patients with familial amyloidosis of the liver, the intestine, the kidney, the heart, peripheral nerves, and in the skin. In addition, some apoA-I variants like apoA-I L178P or L159P have been associated with increased risk of premature coronary heart disease or enhanced progression of carotid intima media thickness, whereas others did not show this association, or were even claimed to have reduced cardiovascular risk and advocated as possible agents for the treatment or prevention of atherosclerosis (notably apoA-I R173CMiiano) [22,43,53]. 

An increased incidence of amyloidosis of the major organs, including the liver, was observed in mice following lifetime exposure to sodium selenate or sodium selenite in drinking water at a level of 0.57 mg selenium/kg/day (Schroeder and Mitchener 1972). This effect was noted in 30% of control mice and 58% (p<0.001) of selenium-treated mice. Data for individual organs were not provided. 

Rhabdomyolysis due to the combination of colchicine with gemfibrozil has been reported in a 40-year-old man with amyloidosis and chronic liver disease (70). 

A physieal examination is necessary to find out if the organs are functioning properly. Blood, urine and bone marrow tests may also be done. A small tissue sample (biopsy) may be taken from the rectum, abdominal fat or bone marrow to determine if the person has amyloidosis. These biopsies are relatively minor procedures done in an outpatient setting with a local anesthetic. Occasionally, samples are taken from the liver, nerve, heart or kidney. This may require hospitalization and can help diagnose the specific oi an affected by amyloidosis. Blood or urine tests can detect the protein, but only bone marrow tests or other small samples of tissue can positively establish the di nosis of amyloidosis. 

Non-specific toxic liver damage may be evident in this connection, possible tuberculostatic toxic effects must also be considered. With severe courses of tuberculosis, peliosis hepatis is often observed. Frequently, retothelial nodules are detectable, as demonstrated for the first time in tuberculosis patients by H. Hamperl in 1953. (50) In the course of chronic pulmonary tuberculosis,infiltration of liver cells was noted, as reported in several publications. (50) It was attributed to toxic effects and/or undernourishment or malnutrition. Secondary hepatic amyloidosis, developing in the course of chronic lung tuberculosis, has also been postulated. (50) A restriction of hepatic function in chronic tuberculosis, which was first observed by E. Leuret et al. in 1922, has been described in a number of publications. (51, 60, 63) Depending on the severity and duration of the disease as well as the tuberculostatic pretreatment, we found pathological laboratory parameters in 15-20% and 25-40% of cases respectively. (50)... 

Complications The following complications have been reported (i.) cholangitis, (2.) obstructive jaundice, (i.) intrahepatic cholelithiasis, (4.) sepsis, (J.) portal hypertension (oesophageal varices, portal vein thrombosis, chronic Budd-Chiari syndrome, etc.), (6.) thrombosis of the inferior vena cava, (7.) amyloidosis, (8.) immune complex-associated glomerulonephritis, (9.) metastases, (10.) acute on chronic liver insufficiency or acute liver failure, and (11.) bronchobiliary fistula. 

Transthyretin amyloidosis (also called familial amyloid polyneuropathy) is an autosomal dominant syndrome characterized by peripheral neuropathy. This disease results from one of five mutations identified thus far in the gene for transthyretin. Transthyretin is also called prealbumin (although it has no structural relationship to albumin) because it migrates ahead of albumin in standard electrophoresis at pH 8.6. Transthyretin is synthesized in the liver and is a normal plasma protein with a concentration of 20-40 mg/dL. It transports thyroxine and retinol binding protein (Chapter 38). The concentration of transthyretin is significantly decreased in malnutrition and plasma levels are diagnostic of disorders of malnutrition (Chapter 17). 

Brandt, K., Cathcart, E. S., and Cohen, A. S., A clinical analysis of the cause and prognosis of forty-two patients with amyloidosis. Am. ]. Med. 44, 955-969 (1968). Brante, G., Kaijser, K., and Ockerman, P. A., Glycogenosis Type I (lack of glucose-6-phosphatase) in four siblings. Acta Paediat. Scand. Suppl. 157, 1-28 (1964). Brensilver, H. L., and Kaplan, M. M., SigniRcance of elevat liver alkaline phosphatase in serum. Gastroenterology 68, 1556-1562 (1975). 

In AL amyloidosis, amyloid is formed from degradation products of the X or k light chains that deposit most frequently in the extracellular matrix of the kidney and the heart but also may deposit in the tongue. In other types of amyloidosis, the amyloid arises from other proteins and deposits in a characteristic organ. For example, the amyloid associated with chronic inflammatory conditions, such as tuberculosis or rheumatoid arthritis, is derived from an acute phase serum protein called serum amyloid Athat is produced by the liver in response to inflammation. It deposits most frequently in the kidney, and cardiac involvement is rare. 

The clinician can determine whether a patient such as Katta Bolic is j mounting an acute phase response to some insult, however subtle, by deter- mining whether several unique acute phase proteins are being secreted by the liver. C-reactive protein, so named because of its ability to interact with the C-polysaccharide of pneumococci, and serum amyloid A protein, a precursor of the amyloid fibril found in secondary amyloidosis, are elevated in patients undergoing the acute phase response and as compared with healthy individuals. Other proteins normally found in the blood of healthy individuals are present in increased concentrations in patients undergoing an acute phase response. These include haptoglobin, certain protease inhibitors, complement components, ceruloplasmin, and fibrinogen. The elevated concentration of these proteins in the blood increases the erythrocyte sedimentation rate (ESR), another laboratory measure of the presence of an acute phase response. 

Daily administration of colchicine is useful for the prevention of attacks of familial Mediterranean fever (familial paroxysmal polyserositis) and for prevention and treatment of amyloidosis in such patients. Colchicine appears to benefit patients with primary biliary cirrhosis in terms of improvement of liver function tests and perhaps of survival. Colchicine also has been employed to treat a variety of skin disorders, including psoriasis and Behcet s syndrome. 

The increase in echogenicity (i. e. increase in density) of a homogeneous, frequently coarsened structure with decreased sound conduction in the form of a structurally dense hver is a reliable indicator of a diffuse liver disease. This increase in intensity and frequency of echoes yields the image of a bright (white) liver (e.g. fatty liver, haemachromatosis). A diffuse liver disease can also be accompanied by a decrease in echogenicity, which is why the hypoechoic liver is known as a dark liver (e. g. acute hver congestion, acute viral hepatitis, amyloidosis), (s. fig. 6.4)... 

AA amyloid appears in a generalized form and is mainly stored perireticularly in the kidney, spleen and liver. This kind of amyloidosis occurs as (1.) a congenital form in cases of familial Mediterranean fever, (2.) an idiopathic (= primary) form without any associated basic disease, and (i.) a reactive (= secondary) form in chronic inflammations or tumours (e.g. Hodgkin s disease) as well as in drug abuse and AIDS. 

VEGF) in patients with advanced solid tumors with liver involvanent (Tabemero et al 2013). Using the DLin-DMA, Alnylam Pharmaceuticals Inc. developed another SNALP encapsulating a siRNA targeting transthyretin (ALN-TTROl) for the treatment of transthyretin mediated amyloidosis (ATTR) that in 2012 completed a phase 1 clinical trial (Table 14.1). 

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