Pulmonary Hypertension

Pulmonary hypertension is defined as a mean pulmonary artery pressure at cardiac catheterisation of  25mmHg or more.

Presentation tends to be progressive breathlessness, and as the condition worsens exertional dizziness and syncope.  Oedema and ascites are late signs.

On examination you might find a loud P2, a systolic murmur of TR, raised JVP, oedema or ascites.

It is classified into 5 groups (NB not all subsets of each of the groups are listed below, just the main ones):

1.  Pulmonary arterial hypertension

• idiopathic (=IPAH)
• heritable - including gene BMPR2
• drug/toxin induced - eg fenfluramine, amphetamines, possibly interferon alpha and beta
• CTD
• HIV infection
• portal HTN
• schistosomiasis
• pulmonary veno-occlusive disease

2.  Pulmonary hypertension due to left heart dysfunction

3.  Pulmonary hypertension due to lung disease/chronic hypoxia 

• COPD
• interstitial lung disease
• sleep-disordered breathing
  

4.  Chronic thromboembolic pulmonary hypertension (CTEPH)

• between 0.5 and 4% of patients develop CTEPH after PE

5.  Pulmonary hypertension with unclear multifactorial mechansms

• haematological disorders - chronic haemolytic anaemia
• sarcoidosis

Prevalence is high in:

• systemic sclerosis (7-12%)
• congenital heart disease (up to 10%)
• portal hypertension (up to 6%)
• HIV (0.5%)

Investigations include: cardiac echo, CXR (cardiomegaly and prominent pulmonary vasculature), BNP, and the definitive investigation is right heart catheterisation.  Investigations would also be undertaken to look for the cause.

Treatment:

• phosphodiesterase-5 inhibitors such as sildenafil or tadalafil
• endothelin receptor antagonists such as bosentan
• prostanoid infusions such as epoprostenol (avoid stopping as this can cause death)
• possibly pulmonary endarerectomy in CTEPH
• possibly high dose calcium channel blockade in IPAH

References
Humbert, M. et al. Guidelines for the diagnosis and management of pulmonary hypertension. European Heart Journal. 2009; 20: 2493-2537.
Kiely, D. et al. Pulmonary hypertesnion: diagnosis and management. BMJ. 2013; 346:f2028.
Simonneau, G. et al. Updated Clinical Classification of Pulmonary Hypertension. J Am Coll Cardiol. 2013; 62(25 Suppl):D34-41.

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Drug Induced Liver Injury

Drug-induced liver injury (DILI) can present as cholestasis, hepatitis or as a mixed picture.  DILI can be either dose-related (eg with paracetamol) or idiosyncratic.   A cholestatic picture of DILI is more common in older patients while a pattern of hepatocellular damage is more common in younger patients.

A persons susceptibility to idiosyncratic DILI is a mixture of genetic predisposition, age, gender (females more susceptible), existing medical conditions (eg diabetes increases severity) and immune factors.

DILI is clinically significant both because it is the leading cause of acute liver injury and also because it is the leading cause of aborted development or withdrawal of otherwise promising drugs.

Drugs associated with DILI include:
- anti HIV agents
- antibiotics  (penicillins - esp co-amoxiclav, macrolides, isoniazid)
- CNS agents (phenytoin, carbamazepine,  sodium valproate, gabapentin, risperidone, tricyclic antidepressants)
- analgesics (NSAIDs, paracetamol)
- antihypertensives (ACE-inhibitors)
- antiglycaemics (metformin, pioglitazone)
- others (atorvastatin, herbal health supplements)

Management:
- stop precipitating drug
- supportive management
- ? n-acetylecysteine

Most patients recover fully from DILI once the offending drug is withdrawn but a small number develop chronic liver disease.

References
Ghabril, M., Chalasani, N. and Bjornsson, E. Drug-induced liver injury: a clinical update. Curr Opin Gastroenterol. 2010; 26(3): 222-226.
Padda, M. et al. Drug induced cholestasis. Hepatology. 2014; 53(4): 1377-1387.
Tajiri, K. and Shimizu, Y. Practical guidelines for diagnosis and management of drug-induced liver injury. Word J Gastroenterol. 2008; 14(44):677
Yuan, L. and Kaplowitz, N. Mechanisms of Drug Induced Liver Injury. Clin Liver Dis. 2013; 17(4): 507-518.

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Progressive multi-focal leucoencephalopathy

Progressive multi-focal leucoencephalopathy (PML) is a demyelinating disease of the central nervous system caused by the JC virus.  Despite many people being infected by the JC virus PML is very rare, generally only occurring in association with conditions such as:

• HIV
• CLL
• patients on natalizumab

Presentations include:

• motor weakness
• impaired vision
• mental changes
• speech abnormalities
• seizures

Investigations

• CT: subcortical hypodensities
• MRI: hyperintense lesions on T2-weighted images, hypointense on T1-weighted images
• CSF: often normal; do PCR on CSF for JC virus

Management:

• in patients with HIV: start HAART
• in patients on natalizumab: stop natalizumab and initiate plasmapheresis

Prognosis: generally very poor. 

References
Berger, J. The clinical features of PML. Cleve Clin J Med. 2011; 78 Suppl 2: S8-12.
Berger, J. and Khalil, K. The pathogenesis of progressive multifocal leukocencephalopathy. Discov Med. 2011; 12(67): 495-503.
Calabrese, L. A rational approach to PML for the clinician. Cleve Clin J Med. 2011; 78 Suppl 2 S38-41.

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Renal cell carcinoma

The classic presentation of renal cell carcinoma (hypernephroma) is the triad of

• flank pain
• haematuria
• flank mass

However, just 10% of patients with RCC present with these symptoms and 40% have none of them at all!

Other presentations include:

• weight loss (30%)
• fever (20%)
• hypertension (20%)
• hypercalcaemia (5%) 

Occasionally they may be associated with a left varicocele.

Renal cell carcinomas may also produce erythropoeitin, resulting in secondary polycythaemia.

Most RCC are sporadic; a minority are familial, for example associated with Von Hippel Lindau.

Treatment is surgical.

References
Cairns, P. Renal cell carcinoma. Cancer Biomark. 2010; 9(1-6): 461-473.

Doshi, D., Saab, M. and Singh, N. Atypical presentation of renal cell carcinoma. J Med Case Rep. 2007; 1: 26.

El-Saeity, N. and Sidhu, P. "Scrotal varicocele, exclude a renal tumour". Is this evidence based? Clin Radiol. 2006; 61(7): 593-599.

Noguchi, Y. et al. Gene expression of erythropoietin in renal cell carcinoma. Intern Med. 1999; 38(12): 991-994.

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Autoimmune hepatitis

Autoimmune hepatitis is a chronic inflammatory liver disease which, untreated, often leads to cirrhosis.

 Presentation

• 25% asymptomatic at diagnosis
• Others:
• fatigue
• pruritis
• anorexia
• nausea
• abdominal pain
• joint pain

Associations

• long-term use of some medications, such as nitrofurantoin or minocycline
• primary biliary cirrhosis - up to 15%
• primary sclerosing cholangitis - up to 8%
• thyroiditis - up to 23%
• diabetes - up to 9%

Investigations

• LFTs - raised AST/ALT
• autoantibodies
• ANA
• SMA
• SLA/LP (soluble liver antigen/liver-pancreas)
• LKM (liver-kidney microsome)
• dsDNA - 15% (specific for either AIH or SLE)
• raised IgG
• negative tests for viral hepatitis
• liver biopsy may show
• lots of plasma cells - 'plasma-cell hepatitis'
• inflammation of hepatocytes at the junction of portal tract and hepatic parenchyma - 'piecemeal necrosis'

Types of AIH:

• Type 1
• 75% of AIH
• ANA/SMA/anti SLA/LP
• all ages
• F:M 3:1
• Type 2
• anti-LKM-1 or anti LC-1
• usually presents in childhood
• F:M 10:1
• more likely to not respond to treatment

Treatment

• corticosteroids
• azathioprine
• lifelong in type 2 AIH; can consider stopping after remission of at least 4 years in type 1 AIH 
• 10-20% of patients will need liver transplants.

Small print gems: In terms of liver diseases, raised IgG suggests AIH, IgM suggests PBC and IgA suggests steatohepatitis (alcoholic or non-alcoholic)

References
Gleeson, D. and Heneghan, M. British Society of Gastroenterology guidelines for management of autoimmune hepatitis. Gut. 2011; 60(12): 1611-1629.
Teufel, A., Galle, P. and Kanzler, S. Update on autoimmune hepatitis. World J Gastroenterol. 2009; 15(9): 1035-1041.

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Obstructive sleep apnoea/hypopnoea syndrome

Obstructive sleep apnoea/hypopnoea syndrome (OSAHS) is a condition in which a person experiences repeated episodes of apnoea/hypopnoea because of closing of the pharyngeal airway during sleep (NICE definition) 

Symptoms 

• Excessive daytime sleepiness 
• Snoring 
• Morning headaches 
• Nocturia 
• Sexual dysfunction 
• Impaired cognition 

Risk factors for OSA

• Increasing age
• Obesity 
• Male gender 
• Enlarged tongue or tonsils 

Conditions associated with OSAHS 

• Marfans 
• Downs 
• Acromegaly 
• Hypothyroidism 

Diagnosis 

• History 
• Sleep study 
• Severity graded on the apnoea/hypnoea index (AHI) 
• Mild: AHI 5-14 
• Moderate: AHI 15-30 
• Severe: AHI >30 

Management 

• Lifestyle changes 
• Weight loss 
• Stop smoking 
• Decrease alcohol 
• Dental devices to keep upper airway open (mild to moderate OSA only)
• CPAP 
• Surgery should only be as part of a clinical trial 

OSAHS increases: 

• Depression 
• Hypertension 
• Increased motor accidents 

References

Eishaug, A. et al. Upper airway surgery should not be first line treatment for obstructive sleep apnoea in adults. BMJ. 2008; 336(7634): 44-45. 

NICE. Continuous positive airway pressure for the treatment of obstructive sleep apnoea/hypopnoea syndrome. 2008. Available at http://publications.nice.org.uk/continuous-positive-airway-pressure-for-the-treatment-of-obstructive-sleep-apnoeahypopnoea-ta139 

Riha, R., Gislasson, T. and Diefenbach, K. The phenotype and genotype of adult obstructive sleep apnoea/hypopnoea syndrome. Eur Respir J. 2009; 33(3):646-655.

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