Autonomic Neuropathy and Chronic Liver Disease

Autonomic neuropathy has been reported in association with alcoholiccirrhosis but there is no information on its occurrence in non-alcoholicliver disease. We have examined autonomic function in 64 patientswith biopsy-proven liver disease (22 with alcoholic liver diseaseand 42 with non-alcoholic liver disease) together with 29 age-matchedcontrols. Forty-five per cent of patients with alcoholic liverdisease and 43 per cent with non-alcoholic liver disease showedevidence of parasyrapathetic damage; 11 per cent of patientswith alcoholic liver disease and 12 per cent with non-alcoholicliver disease had sympathetic damage. Forty-five per cent ofpatients with alcoholic liver disease and 22 per cent with non-alcoholicliver disease had peripheral neuropathy on clinical examination.Sixty-eight per cent of those with peripheral neuropathy alsohad autonomic neuropathy. This study confirms that autonomicneuropathy is common in alcoholic patients but the fact thatit is found with comparable frequency in non-alcoholic liverdisease suggests that the neurological defect may be secondaryto the disturbed liver function. The implications of these observationswith regard to prognosis of chronic liver disease are discussed.     

The influence of autonomic neuropathy on mortality in insulin-dependent diabetes

Five-year survival was investigated in 506 randomly selected patients with insulin-dependent diabetes mellitus screened for autonomic neuropathy with a series of cardiac autonomic function tests. Of the 484 diabetics traced, 44 (9 per cent) had died. The cumulative 5-year mortality rate was increased more than five-fold in those with autonomic neuropathy: 27 per cent vs. 5 per cent in those with normal autonomic function. Discriminant analysis of survivors and non-survivors showed that autonomic neuropathy was the most important independent predictor of death. Among those who died, autonomic neuropathy was associated with an increased frequency of retinopathy and peripheral neuropathy and a slightly lower frequency of macrovascular disease. Autonomic neuropathy was associated with an increased mortality rate from renal failure, but not from any other causes.     

The Influence of Autonomic Neuropathy on Mortality in Insulin-dependent Diabetes

Five-year survival was investigated in 506 randomly selectedpatients with insulin-dependent diabetes mellitus screened forautonomic neuropathy with a series of cardiac autonomic functiontests. Of the 484 diabetics traced, 44 (9 per cent) had died. The cumulative 5-year mortality rate was increased more thanfive-fold in those with autonomic neuropathy: 27 per cent vs.5 per cent in those with normal autonomic function. Discriminantanalysis of survivors and non-survivors showed that autonomicneuropathy was the most important independent predictor of death.Among those who died, autonomic neuropathy was associated withan increased frequency of retinopathy and peripheral neuropathyand a slightly lower frequency of macrovascular disease. Autonomicneuropathy was associated with an increased mortality rate fromrenal failure, but not from any other causes.     

1-14C]Ethanol breath test in alcoholic liver disease

The activity of ethanol metabolising enzymes was assessed in 51 patients with alcoholic and non-alcoholic liver disease using tracer doses of [1-14C]ethanol and measuring 14CO2 excretion in the breath. Alcoholic patients with only fatty infiltration of the liver showed significantly increased activity compared with controls. Comparing alcoholic patients with cirrhosis and a serum albumin greater than 28 g/l, activity in those with a recent history of continued heavy drinking was significantly greater than in patients who had abstained from alcohol. In addition, both groups of alcoholic cirrhosis showed significantly more activity than patients with non-alcoholic cirrhosis. The activities of patients with acute alcoholic or viral hepatitis were normal when their prothrombin times were less than 7 sec prolonged, but were reduced when prolongation exceeded 7 sec. These results demonstrate that in chronic alcoholic liver disease, even with cirrhosis, alcohol can still increase the activity of ethanol oxidising enzymes provided hepatic function remains adequate. However, this response is lost in acute liver damage and in chronic alcoholic disease with severe hepatic dysfunction.     

The Natural History of Diabetic Autonomic Neuropathy

Seventy-three diabetics (62 males and 11 females) who complainedof symptoms suggestive of autonomic neuropathy were followedprospectively for up to five years. Thirty patients presentedwith impotence alone, while the other 43 presented with oneor more of the following: postural hypotension, intermittentdarrhoea, hypoglycaemic unawareness, sweating abnormalitiesand gastric fullness. Most subjects with impotence alone hadnormal autonomic function tests (responses to the Valsalva manoeuvreand sustained handgrip) whereas the majority with other symptomshad abnormal tests. Twenty-six subjects (20 males and six females) died during thefollow-up period. Of the 33 with initially normal autonomicfonction tests, five (15 per cent) died, whereas of the 40 withinitially abnormal tests, 21 (53 per cent) died. Diabetics withsymptoms of autonomic neuropathy and abnormal autonomic functiontests, had a calculated mortality rate after two-and-a-halfyears of 44 per cent and after five years of 56 per cent. Halfthe deaths in those with abnormal tests were from renal failure,and the remainder were either sudden and unexpected, or fromother causes which may have been associated with the autonomicnearopathy. Autonomic function testing repeated during the follow-up periodshowed that some normal tests later became abnormal, but oncetests were abnormal, they usually remained abnormal. A numberof subjects with impotence alone developed other features ofautonomic neuropathy and abnormal tests during the follow upperiod. Symptoms of autonomic neuropathy, particularly postural hypotension,gastric symptoms and hypoglycaemic unawareness, together withabnormal autonomic function tests, carry a very poor prognosis.Diarrhoea and impotence, on their own, cannot be relied on assymptoms of autonomic neuropathy. Autonomic function testingusing simple cardiovascular reflexes give a good guide to theprognosis of diabetic autonomic neuropathy.     

Sex hormone changes in chronic liver disease: a matched study of alcoholic versus non-alcoholic liver disease

Men with liver disease are hypogonadal and feminized. European workers consider the liver disease itself to be the major factor but American workers blame alcohol consumption. We studied sexual dysfunction and sex hormones in three matched groups of men; controls (n = 22), those with alcoholic liver disease (n = 21), and those with non-alcoholic liver disease (n = 21). Men with alcoholic liver disease had more sexual dysfunction. Testosterone and androstenedione concentrations were lower and oestradiol and dehydroepiandrosterone sulphate levels were raised in the liver disease groups. The changes were greatest in the alcoholic liver disease group. In this, the first controlled study, liver disease per se appears to cause sexual dysfunction and sex hormone changes but these changes are amplified by ethanol.     

Progression of diabetic autonomic neuropathy over a decade in insulin-dependent diabetics

The prognosis for diabetics with autonomic neuropathy is little known. We therefore studied the progress of young insulin-dependent diabetics, first identified as having abnormal autonomic function 10-15 years ago. We have shown that the mortality of diabetics with symptomatic autonomic neuropathy is increased, but is less than previously reported. Mortality in asymptomatic diabetics with an isolated abnormality in autonomic function tests is not increased. The heart rate variability declines at 1.02 +/- 0.47 (SD) per annum in diabetics with an initially normal heart rate variability. While symptoms of autonomic neuropathy do not usually remit even over a decade, they do not commonly progress. Three groups of young insulin-dependent diabetics had heart rate variability tested between 1972 and 1977 and have been reviewed 10-15 years later. Group A (n = 49) had symptomatic autonomic neuropathy and an abnormal heart rate variability (less than 12), Group B (n = 24) were asymptomatic yet had an abnormal heart rate variability and Group C (n = 38) were asymptomatic and had a normal heart rate variability (16-26). The 10-year survival in Group A (73.4 per cent) was less (P less than 0.05) than in Groups B (91.7 per cent) or C (89.5 per cent) which did not differ from each other. The 18 Group A deaths were due predominantly to renal failure (n = 4), myocardial infarction in patients with nephropathy (n = 3) and sudden unexpected death (n = 3). The chief symptoms of autonomic neuropathy--diarrhoea, postural hypotension and gustatory sweating, were very persistent but did not necessarily deteriorate or become disabling in the majority of patients. The development of autonomic symptoms in asymptomatic patients with abnormal heart rate variability was uncommon over a decade.     

Alcoholic skeletal myopathy, a clinical and pathological study

One hundred and fifty-one inpatients with a history of chronic heavy alcohol intake were examined for evidence of muscle disease. Ninety-two patients (60 per cent) had histologically abnormal biopsies of the quadriceps muscle. The most common abnormality, which was often severe, was type II muscle fibre atrophy. Seven patients (5 per cent) had histological evidence of acute myopathy, one of whom presented with the full clinical picture of acute rhabdomyolysis. Twenty-three patients had cirrhosis, 36 were significantly malnourished and 98 had evidence of a peripheral neuropathy. None of these features, however, were sufficient to account for the muscle abnormalities. There was no clear relationship between musculo-skeletal symptoms and muscle biopsy histology. Serum creatine kinase activity was elevated in only 23 subjects and was an insensitive indicator of subclinical acute myopathy and of chronic alcoholic myopathy. Follow-up studies after abstinence from alcohol invariably showed both objective and subjective improvement of muscle function - often in the absence of any clinical recovery from the peripheral neuropathy. Continued alcohol consumption was accompanied by persistence and often deterioration of muscle fibre atrophy. It is concluded that chronic skeletal myopathy is a frequent consequence of alcohol abuse and may result from a direct toxic effect of ethanol on muscle fibres.     

Progression of Diabetic Autonomic Neuropathy over a Decade in Insulin-Dependent Diabetics

The prognosis for diabetics with autonomic neuropathy is littleknown. We therefore studied the progress of young insulin-dependentdiabetics, first identified as having abnormal autonomic function10–15 years ago. We have shown that the mortality of diabeticswith symptomatic authonomic neuropathy is increased, but isless than previously reported. Mortality in asymptomatic diabeticswith an isolated abnormality in autonomic function tests isnot increased. The heart rate variability declines at 1.02±0.47(SD) per annum in diabetics with an initially normal heart ratevariability. While symptoms of autonomic neuropathy do not usuallyremit even over a decade, they do not commonly progress. Three groups of young insulin-dependent diabetics had heartrate variability tested between 1972 and 1977 and have beenreviewed 10–15 years later. Group A (n=49) had symptomaticautonomic neuropathy and an abnormal heart rate variability(<12), Group B (n=24) were asymptomatic yet had an abnormalheart rate variability and Group C (n=38) were asymptomaticand had a normal heart rate variability (16–26). The 10-yearsurvival in Group A (73.4 per cent) was less (P<0.05) thanin Groups B (91.7 per cent) or C (89.5 per cent) which did notdiffer from each other. The 18 Group A deaths were due predominantlyto renal failure (n=4), myocardial infarction in patients withnephropathy (n=3) and sudden unexpected death (n=3). The chiefsymptoms of autonomic neuropathy-diarrhoea, postural hypotensionand gustatory sweating, were very persistent but did not necessarilydeteriorate or become disabling in the majority of patients.The development of autonomic symptoms in asymptomatic patientswith abnormal heart rate variability was uncommon over a decade.     

Effect of liver disorders on ethanol elimination and alcohol and aldehyde dehydrogenase activities in liver and erythrocytes

1. Liver biopsies were performed in healthy control subjects and in subjects with alcoholic and non-alcoholic liver disease in order to examine alcohol dehydrogenase (ADH; EC 1.1.1.1) and aldehyde dehydrogenase [ALDH; aldehyde dehydrogenase (NAD+); EC 1.2.1.3] activities. Erythrocyte ALDH and ethanol metabolism were also investigated in the same subjects. 2. Fifteen per cent of the subjects studied (seven of 48 subjects tested) presented atypical ADH activity, characterized by elevated activity at pH 7.4 or 8.8 compared with that found in subjects with the usual ADH form. However, the ethanol elimination curves obtained in two subjects with atypical ADH were indistinguishable from the kinetics of the group with normal ADH. Subjects displaying atypical ADH activity showed normal liver and erythrocyte ALDH activities. 3. Considering only the subjects with the normal ADH form, hepatic ADH activity was unaltered in subjects with non-alcoholic liver disease (chronic hepatitis or cirrhosis) and in those with alcoholic steatosis. Subjects with alcoholic hepatitis or alcoholic cirrhosis showed a lower ADH activity compared with the healthy control group. 4. In spite of the changes detected in subjects with alcoholic liver disease, curves of blood ethanol concentration after oral administration of 0.4 g of ethanol/kg were indistinguishable between the alcoholic hepatitis group and the control group. 5. Hepatic ALDH activity, assayed at 300 mumol/l acetaldehyde, was found to be diminished in all liver pathologies investigated, regardless of their aetiology. Nevertheless, erythrocyte ALDH activity was not modified in subjects with non-alcoholic or alcoholic liver disease. As a result of these findings, no relationship was found between hepatic and erythrocyte ALDH.(ABSTRACT TRUNCATED AT 250 WORDS)     

Erythrocyte aldehyde dehydrogenase activity in alcoholic subjects and its value as a marker for hepatic aldehyde dehydrogenase in subjects with and without liver disease

Erythrocyte aldehyde dehydrogenase activity was assayed in actively drinking alcoholics, patients with alcoholic liver disease who claimed to be abstaining, patients with non-alcoholic liver disorders and normal controls. Hepatic cytosolic aldehyde dehydrogenase was also assayed in the majority of the subjects. Actively drinking alcoholics had significantly lower erythrocyte aldehyde dehydrogenase activity than controls (P less than 0.01) but abstaining alcoholic liver disease and non-alcoholic liver disorder subjects did not. There was a significant correlation between erythrocyte and hepatic cytosolic aldehyde dehydrogenase activity in the control group (r = 0.94, P less than 0.05) but not in the other study groups.     

Autonomic neuropathy in diabetes mellitus, chronic renal failure and liver cirrhosis

Chronic diseases (diabetes mellitus, end stage renal failure on hemodialysis, post-hepatitic liver cirrhosis) caused autonomic neuropathy in 34 of 65 cases. The frequency of autonomic neuropathy was 14 of 30 diabetics (typ I and typ II), twelve of 19 patients on dialysis, and eight of 16 non-alcoholic liver cirrhotics. We did not find a correlation between the tests of the cardiovascular and of the gastrointestinal system. The distribution of the neuropathic changes was undependent of the underlying disorder. Using appropriate tests, alterations of the autonomic functions can be discovered frequently even in asymptomatic patients. At least two pathological test results are necessary to reach a significant difference between patients and healthy controls. This indicates that the diagnosis of autonomic neuropathy should rely on two or more pathological test results. The evidence of autonomic neuropathy identifies a population of high risk patients.     

Inducing efficacy of ethanol on hepatic drug metabolizing enzymes in patients

In liver biopsy material of eighty-nine patients with suspected liver disease the drug-metabolizing function was investigated. The capacity of the liver to oxidatively metabolize drugs was assessed by determination of cytochrome P-450 dependent monooxygenase activity in vitro. The biotransformational function of these microsomal enzymes was tested with compounds representing the activity of oxidative drug metabolism (7-ethoxycoumarin, p-nitroanisol and cytochrome c). From the eight-nine patients sixty-one had various liver diseases not related to ethanol and twenty-eight abused ethanol. When both groups were matched for age, sex, smoking, treatment with sedatives, drugs and degree of liver damage the alcoholic group had significantly higher activities of 7-ethoxycoumarin O-deethylase (EOD: 76.9 +/- 31.1 pmol min-1 mg-1 protein, mean +/- SD) than the non-alcoholic liver disease group (42.7 +/- 14.1). The inducing effect of ethanol was most striking on the EOD activity, less for the O-demethylation of p-nitroanisol (PNA) and not present for the NADPH-cytochrome c reductase. The induced patients were analysed in detail to find out which factors were responsible for the observed scatter of enzyme activities within the alcoholic group. Alcoholics with fatty liver (n = 7) had the highest EOD activities (108.9 +/- 25.0), patients with alcoholic hepatitis (n = 10) had significantly less activity (66.0 +/- 1.9) than the former group. However, alcoholics without liver damage (n = 6) had activities not significantly different (46.0 +/- 15.8) from controls (39.4 +/- 9.1). These subgroups among the alcoholics were comparable in terms of sex, age, smoking and drinking habits.(ABSTRACT TRUNCATED AT 250 WORDS)     

Peripheral nerve dysfunction in scleroderma.

Peripheral neuropathy in patients with scleroderma is thought to be rare. We have undertaken a quantitative assessment of peripheral nerve function in 29 patients with either limited cutaneous scleroderma or progressive systemic sclerosis. Tactile thresholds were raised in the fingers in 28 per cent of patients and in the foot in 50 per cent. Two-point discrimination was abnormal in 10 patients, thermal thresholds were abnormal in five and vibration thresholds were abnormal in one. Nerve conduction studies showed abnormalities in six patients, five of whom had clinical signs of a mild peripheral neuropathy: the mean duration of disease in these six patients was 10 years longer than that in the remainder of the patients. There was electrophysiological evidence of a subclinical carpal tunnel syndrome in two patients. The sympathetic skin response was recorded in 16 patients who had not been subjected to sympathectomy for Raynaud's phenomenon, and was abnormal in four. These results indicate that peripheral nerve dysfunction in scleroderma, though mild, is not as uncommon as previously thought. The abnormal cutaneous sensory thresholds may be partly due to altered viscoelastic properties of the skin, but abnormal responses in the lower limbs to tests of tactile sensitivity, the clinical findings and the disturbances of nerve conduction argue in favour of an additional neuropathic process in some patients. Low grade distal nerve trunk ischaemia may be responsible.     

Sex Hormone Changes in Chronic Liver Disease: A Matched Study of Alcoholic versus Non-alcoholic Liver Disease

Men with liver disease are hypogonadal and feminished. Europeanworkers consider the liver disease itself to be the major factorbut American workers blame alcohal consumption. We studied sexualdysfunction and sex hormones in three matched groups of men;controls (n=22), those with alcoholic liver disease (n=21),and those with non-alcoholic liver disease (n=21). Men withalcoholic liver disease had maore sexual dysfunction. Testosteroneand androsastenedione concentrations were lower and oestradiaoland dehydroepiandrosterone sulphate levels were raised in theliver disease groups. The changes were greatest in the alcoholicliver disease group. In this, the first controlled study, liverdisease per se appeares to cause sexual dysfunction and sexhormone changes but these changes are amplified by ethanol.     

Familial amyloidosis: a study of 52 North American-born patients examined during a 30-year period.

Between 1961 and 1990, 52 patients with biopsy-proven familial amyloidosis born in North America were examined at the Mayo Clinic. At the time of diagnosis of familial amyloidosis, 83% of these patients had peripheral neuropathy, 33% had autonomic neuropathy, and 27% had cardiomyopathy. Renal disease was noted in fewer than 10%, and liver involvement was rare. The median age at diagnosis was 64 years. The sensitivity of various diagnostic biopsies was similar to that for primary amyloidosis: deposits of amyloid were found in 77 and 78% of the subcutaneous fat aspirates or rectal biopsy specimens, respectively, and in 41% of specimens of bone marrow. The median duration of survival of 5.8 years for patients with inherited amyloidosis was superior to that for patients with primary amyloidosis. When patients were stratified by organ involvement, the survival of patients with familial amyloidosis remained superior. The presence of cardiomyopathy and an interactive variable of age and the presence of autonomic neuropathy were powerful predictors of survival. Of the 52 patients, 22 died, 12 (55%) of cardiac failure or cardiac arrhythmia. Nine patients (41%) died of inanition in conjunction with progressive peripheral or autonomic neuropathy. Transthyretin was identified by immunohistochemical studies in 31 of the 34 tissue specimens tested. A transthyretin mutation was identified in 24 of the 31. A transthyretin mutation was found in five additional patients for whom tissue was unavailable for immunostaining.     

The Liver in Ulcerative Colitis

Clinical, haematological, biochemical, bacteriological, histological,and immunological data in 300 patients with ulcerative colitishave been examined with special reference to liver disease anddysfunction. Biochemical dysfunction of the liver is common. Forty-five patients(15 per cent) had an abnormality of one or more of the threebasic tests of liver dysfunction used in this study: the bromsulphthaleinretention test, the serum glutamate pyruvate transaminase, andthe alkaline phosphatase. Further biochemical tests contributedlittle additional information. A considerable proportion of patients with biochemical liverdysfunction had no histological abnormality in biopsy material.Conversely, a number of patients with normal biochemical findingshad pathological changes in liver biopsy specimens. In almostall patients in this group the pathological changes were ofa minor nature. Thirty-one patients (10-3 per cent) had one or more pathologicalchanges in their liver biopsy specimens. Fatty change was thecommonest occurring in 19 patients (6·3 per cent); andit was the principal change in 14 (4·7 per cent). Pericholangitisoccurred in 15 patients (5 per cent) and was the principal findingin 12 (4 per cent). Chronic liver disease was infrequent andoccurred in only four patients (1·3 per cent); threepatients with post-necrotic cirrhosis and one patient with chronicactive hepatitis. One patient had severe amyloid infiltrationof the liver. Culture of liver tissue for bacteria and L forms was negative. Immunological tests showed a number of patients with a positiveimmuno-fluorescent test for human colon (25 patients or 12·7per cent) and for antinuclear factor (8·9 per cent).Tests for thyroglobulin antibodies were positive in 29 patients(10·8 per cent). No relationship was found between hepaticlesions and any of the positive immunological tests. Immunoglobulinassay did not show striving changes in those patients with liverdisease or dysfunction. In ulcerative colitis, minor pathological changes in the liverare more frequent than overt chronic liver disease. The presenttype of study almost certainly underestimates the frequencyof major liver disease in ulcerative colitis because this particularcombination carried a poor prognosis. The question of whetherpericho-langitis is the common precursor of post-necrotic cirrhosiscannot be answered at present, but the data now available willprovide the solution if the same patients are kept under observationfor a number of years. The aetiology of the hepatic lesions remains obscure but somedeductions can be drawn from the present data. From clinicalconsiderations, the overt liver disease appears to behave likea viral hepatitis which has become chronic. There is no evidenceto support the view that homologous serum hepatitis from bloodtransfusion is the significant factor. Drugs do not appear tobe of any great relevance. Immunological relationships are essentiallynegative. Portal bacteraemia appears to be an unlikely causeof the overt chronic liver disease encountered in the presentstudy.     

Splenic influences on the blood in chronic liver disease

The influence of the spleen on the blood has been assessed in a series of 187 consecutive patients with chronic liver disease. Patients were described as having 'hypersplenism' if the white blood count and/or platelet count were below 4.0 X 10(9)/1 and 100 X 10(9)/1 respectively at the time of biopsy diagnosis and on at least one subsequent occasion. Using this definition 17 per cent of patients with alcoholic cirrhosis had hypersplenism, compared with 38 per cent with cryptogenic cirrhosis and 26 per cent with active chronic hepatitis. Studies with 51Cr labelled autogenous erythrocytes in 36 of the patients with different types of chronic liver disease showed that the spleen rarely caused anaemia either by excessive splenic pooling or splenic haemolysis. Further studies with 51Cr labelled platelets in 20 other patients showed that the splenic platelet pool was usually considerably increased and the platelet life span reduced. Some patients showed excessive destruction of platelets in the spleen but none of these features consistently related to thrombocytopenia. Splenic enlargement per se did not cause expansion of the plasma volume in chronic liver disease. Of a total of 17 patients who underwent surgical operations for reduction of portal pressure five had hypersplenism but in these the haematological state was not significantly improved at one month. However, none of the survivors of these operations subsequently developed hypersplenism. One patient with severe hypersplenism who underwent simple splenectomy was cured of leucopenia but not of thrombocytopenia.