Non-Liver Related Conditions Associated With Hepatitis C

[Guest guest]

This is from the November 2000's HCV Advocate:

(http://www.hcvadvocate.org/)

Non-Liver Related Conditions Associated With Hepatitis

C

By Dr Ed Gane

Hepatologist

New Zealand Liver Transplant Unit

Introduction Recent studies have clearly demonstrated

that people with

chronic hepatitis C infection have a reduced

health-related quality of

life, which improves again following successful

antiviral therapy. In

addition, non-liver manifestations of hepatitis C

infection have been

observed in almost every body system including skin,

kidney, blood,

lymphatic system, nervous system, salivary gland,

thyroid and lung (see

Table 1).

In a recent French study of 321 patients attending

Hepatitis C clinic,

one

third of patients had at least one of these

conditions. The onset of

these

extrahepatic conditions is unrelated to severity of

liver damage,

duration

of infection, mode of transmission, HCV genotype, or

age.

Interestingly,

thyroid disease is more common in women, reflecting

the female

preponderance in the general population.

Causes

The mechanisms of the non-liver tissue damage are

either direct effects

of

the HCV infection or indirect effects of the body’s

immune response to

HCV. Examples of direct infection by HCV include

Porphyria cutanea

tarda

(PCT), Sicca syndrome and cryoglobulinaemia. PCT is a

blistering skin

condition, caused by a direct blocking effect of HCV

on enzyme pathways

within the liver cell. The dry mouth seen in

HCV-induced Sjogren’s

syndrome is a direct effect of the HCV infection of

the lining of

salivary

gland ducts, leading to salivary gland injury. Chronic

infection of

lymphoid tissue is thought to be the initial step in

the development of

the lymphoproliferative complications of HCV-

cryoglobulinaemia

(common)

and lymphoma (very rare).

Indirect effects of the body’s immune response include

both autoimmune

and

immune-complex diseases. Examples of autoimmune

diseases associated

with

chronic Hepatitis C infection include haemolytic

anaemia,

thrombocytopaenia (low platelets), lichen planus (a

rare skin rash

usually

on the forearms and inside the mouth) and thyroiditis.

In these

conditions

the body can no longer distinguish between viral

proteins and our own

tissue proteins. HCV-induced antibodies target our own

own tissue

proteins, leading to tissue injury rather than viral

inactivation. This

confusion arises either because viral proteins are

identical to our own

tissue proteins (so-called “molecular mimicry”), or

because the virus

itself alters the infected tissue’s proteins so that

our immune system

no

longer recognises them as “self” but sees them as

foreign, leading to

an

immune response. In immune complex disease, excess

levels of

HCV-specific

antibodies complex together with their target viral

proteins. These

complexes are circulating within the bloodstream which

may injure skin,

nerves, kidneys and other organs by occluding

(blocking) or causing

inflammation in small blood vessels which supply these

tissues.

Cryoglobulinaemia

The most common extrahepatic manifestation (illness

occuring outside of

the liver) of hepatitis C infection is essential mixed

cryoglobulinaemia

(EMC). This syndrome presents as a red, raised, skin

rash, which

usually

appears first on the shins and feet. The rash

fluctuates but is usually

worse in winter. Other commonly associated symptoms

include sore joints

and fever. Less commonly, the rash may occur in the

kidney

(glomerulonephritis) leading to loss of protein in the

urine and

occasionally kidney failure (see below) or in the gut,

causing severe

pain

requiring emergency surgery.

The rash and other problems of EMC are caused by

cryoglobulins, which

are

immune complexes of HCV proteins and anti-HCV

antibodies bound together

by

Rheumatoid factor, which is a special protein produced

by lymphocytes

infected with HCV. They clump together when the blood

temperature falls

below normal and dissolve again at body temperature.

In the small

superficial blood vessels of the skin, the blood slows

down and cools.

This causes the cryoglobulins to clump together and

block the blood

vessels, thus leading to inflammation and the

development of skin rash

characteristic of EMC. First described in 1966, EMC

was initially

associated with chronic non-A, non-B hepatitis.

However, the introduction of reliable HCV serological

testing in 1990

demonstrated that most (between 50% and 98%) patients

with EMC had

chronic

HCV infection. The typical symptoms of essential mixed

cryoglobulinaemia

(EMC) occur in around 5% of patients with chronic HCV

infection. Other

common symptoms of EMC include fever and sore joints.

Diagnosis of EMC

is

based on the detection of cryoglobulins in the blood

in someone with

rash

or other features of EMC. Occasionally, biopsy of the

skin rash, kidney

or

other affected organs is also required to confirm the

diagnosis, prior

to

treatment.

To ensure accurate determination of cryoglobulins in

the blood, special

collection of the blood sample is necessary: it must

be placed

immediately

into a thermos heated to body temperature (37C) and

kept at this

temperature until separated in the laboratory

centrifuge. Using such

techniques, circulating cryoglobulins will be found in

almost 30% of

patients with chronic HCV infection - i.e. most

patients with

cryoglobulins will have EMC without any symptoms of

the condition.

Cryoglobulins are more common in patients with

long-standing HCV

infection

and in those with cirrhosis. This is because clearance

of circulating

immune complexes by the liver macrophage cells is

reduced in cirrhosis.

Treatment of EMC (skin rash, arthritis, etc) is

treatment of the

underlying HCV infection i.e. antiviral therapy with

interferon with or

without ribavirin. The HCV eradication rates achieved

with antiviral

therapy are similar to those in patients without

cryoglobulins.

Eradication of the HCV is accompanied by reduction in

the cryoglobulins

and resolution of the skin rash.

In patients who have ongoing complications of

cryoglobulins and who

have

not responded to antiviral therapy, other treatments

may be necessary,

including cyclophosphamide and prednisone. These drugs

are

“immunosuppressants” which work by either reducing the

production of

the

cryoglobulins or suppressing the local inflammation in

the tissues

caused

by the cryoglobulins. Unfortunately, they increase the

amount of

circulating HCV. Therefore, they should be used after

rather than

before

antiviral therapies, because their use will prevent

later response to

interferon and ribavirin. Cryoglobulinaemia should be

considered a mild

form of abnormal lymphocyte proliferation. Sometimes

the abnormal

lymphocytes have a specific DNA mutation, which is

also found in

certain

types of low-grade lymphomas. In those countries with

high rates of HCV

infection, an increased rate of lymphoma is observed

in patients with

HCV

infection, suggesting a definite but rare link between

these 2

conditions.

Kidney disease

HCV is found in 2-10% of people on long-term

haemodialysis and in 2-5%

of

those who received kidney transplants prior to 1990.

This is not

because

HCV caused the kidney disease, but because these

patients with severe

kidney disease became infected through exposure to

blood products or

kidneys from HCV+ donors (prior to 1990 when routine

screening for HCV

was

introduced). Rarely is HCV the cause of the kidney

disease. In these

cases, the kidney disease results from precipitation

of circulating

immune

complexes in the small blood vessels of the filtering

units of the

kidney

(glomeruli), leading to leaky kidneys which lose

protein into the

urine.

Cryoglobulins are present in about half the cases.

Interferon

monotherapy,

aimed at clearing the HCV infection, is the best

treatment for this

kidney

disease. HCV clearance reduces protein loss and

improves kidney

function.

Ribavirin must not be used as it causes severe anaemia

in people with

kidney disease.

Porphyria cutanea tarda

Porphyria cutanea tarda is a skin condition where the

face, hands, neck

blister after either minor trauma or exposure to

sunlight.

Unlike the rash associated with cryoglobulinaemia, the

rash of PCT is

usually worse in the summer months and less in winter,

related to the

amount of sunlight. The skin sensitivity is because of

build-up of

porphyrins in the blood. Porphyrins are by-products of

haemoglobin

production, which are usually present in the body in

only minute

quantities. They accumulate only when the enzyme

pathway which breaks

down

porphyrins is insufficient. Total lack of this enzyme

is a very rare

inherited disorder. Much more common is an inherited

partial deficiency

of

the enzyme which only becomes apparent when the liver

is further

damaged

by another disease such as alcohol, iron overload (due

to another

inherited gene mutation), or chronic viral hepatitis.

In countries with high rates of HCV infection (Italy,

Japan, Spain),

70-90% of people with PCT are HCV positive, whilst in

countries with

low

rates of HCV (Ireland, Australia and New Zealand),

10-30% of people

with

PCT have hepatitis C. Heavy alcohol use may aggravate

this condition by

further damaging the liver cell enzyme pathways.

Management of PCT

involves simple measures designed to protect the

fragile skin, from

sunlight and from trauma. Oestrogen-containing

medications (increase

porphyrin production) and heavy alcohol use (reduce

porphyrin

breakdown)

should be avoided. The mainstay of PCT treatment in

HCV+ patients

should

be antiviral therapy with interferon and ribavirin.

Successful HCV

clearance is associated with long-term remission of

the skin disorder.

Sicca syndrome

Almost 50% of patients with chronic HCV will have HCV

detectable in

saliva

[though not in sufficient quantity to allow

transmission], many of whom

will complain of dry eyes or a dry mouth (with taste

disturbance).

Laboratory tests demonstrate reduced rates of tear and

saliva

production

and biopsy of the salivary glands show a

characteristic picture of

inflammation, attributable to the local HCV infection.

The mouth

dryness

is exacerbated by the side-effects of methadone

maintenance. It is very

important for such patients to be meticulous with

regards to dental

hygiene, in order to prevent severe dental caries

(tooth decay) and

gingivitis (inflammation of gums). Symptomatic relief

can be obtained

by

using artificial tears and saliva. In one study of 8

HCV patients with

Sicca syndrome, eradication of HCV with interferon was

accompanied by

increase of saliva production back to normal.

Thyroid disease

Thyroid hormone is responsible for maintaining the

normal metabolic

rate.

Thyroid diseases can be divided into hyperthyroidism

when the thyroid

is

overactive (often resulting in sweating, weight loss,

anxiety and

diarrhoea) and hypothyroidism when the thyroid is

underactive (often

resulting in weight gain, tiredness, dry skin and

constipation).

Both hyperthyroidism and hypothyroidism are much more

common in women

than

men and are usually preceded by the development of

anti-thyroid

antibodies. Although anti-thyroid antibodies are more

common in women

with

HCV (25 - 30%) compared to women without HCV infection

(10 - 15%),

there

is no associated increase in the rate of thyroid

disease in the absence

of

Interferon therapy. However, Interferon (with or

without ribavirin) is

associated with the onset of hypothyroidism in 20% of

HCV+ women. The

reason for this interferon effect is probably

two-fold: an indirect

effect

of interferon, enhancing our immune responses (thereby

triggering

previously latent autoimmune thyroid disease) and a

direct toxic effect

on

the thyroid gland (blocking formation of the normal

thyroid hormones).

Risk factors for developing thyroid disease during

interferon therapy

are:

female, age > 50 years, pre-existing antithyroid

antibodies (of whom

75%

will develop thyroid disease during interferon).

Antithyroid antibodies

should be checked in all patients prior to commencing

interferon and

thyroid function tests should be tested before

starting at 6 months and

12

months therapy. Usually, if hypothyroidism develops,

interferon can be

continued with addition of thyroxine tablets. Most,

but not all, cases

of

thyroid disease improve after completion of therapy.

Summary Around one

third of people with chronic hepatitis C infection

will develop some

extrahepatic condition of HCV infection, which is

either a direct

result

of HCV infection of that organ or is caused by the

body’s immune

response

to HCV.

These extrahepatic conditions progress independently

of the liver

disease.

People with minimal liver disease may have severe

extrahepatic disease.

Most of these conditions will improve following

eradication of HCV with

antiviral therapy, with the exception of thyroid

disease, which may

first

develop during Interferon therapy. Extrahepatic

conditions should be

regarded as indications for starting antiviral

therapy.

Reprinted with permission from the Hep C Review, New

South Wales,

Australia, Ed 30, Sept 2000.

__________________________________________________