Valproic acid and nonalcoholic fatty liver disease: A possible association?

Table 1 Nonalcoholic steato-hepatitis Clinical Research Network Scoring System (adapted from ref. [3])

Item	Definition		Score/code
Steatosis
	Grade	Low-to medium-power evaluation of parenchymal involvement by steatosis
		< 5%	0
		5%-33%	1
		> 33%-66%	2
		> 66%	3
	Location	Predominant distribution pattern
		Zone 3	0
		Zone 1	1
		Azonal	2
		Panacinar	3
	Microvesicular steatosis	Contiguous patches
		Not present	0
		Present	1
Fibrosis
	Stage	None	0
		Perisinusoidal or periportal	1
		Mild, zone 3, perisinusoidal	1A
		Moderate, zone 3, perisinusoidal	1B
		Portal/periportal	1C
		Perisinusoidal and portal/periportal	2
		Bridging fibrosis	3
		Cirrhosis	4
Inflammation
	Lobular inflammation	Overall assessment of all inflammatory foci
		No foci	0
		< 2 foci per 200 × field	1
		2-4 foci per 200 × field	2
		> 4 foci per 200 × field	3
	Microgranulomas	Small aggregates of macrophages
		Absent	0
		Present	1
	Large lipogranulomas	Usually in portal areas or adjacent to central veins
		Absent	0
		Present	1
	Portal inflammation	Assessed from low magnification
		None to minimal	0
		Greater than minimal	1
Liver cell injury
	Ballooning	None	0
		Few balloon cells	1
		Many cells/prominent ballooning	2
	Acidophil bodies	None to rare	0
		Many	1
	Pigmented macrophages	None to rare	0
		Many	1
	Megamitochondria	None to rare	0
		Many	1
Other findings
	Mallory's hyaline	Visible on routine stains
		None to rare	0
		Many	1
	Glycogenated nuclei	Contiguous patches
		None to rare	0
		Many	1

Table 2 Main side effects of valproic acid

GI disorders: an increase of liver enzymes is common, particularly in early treatment, and it may be transient. Nausea and diarrhea occur frequently at the beginning of treatment, but disappear after a few days without discontinuing treatment. Rare cases of pancreatitis have been reported

Nervous system disorders: transient side effects such as dizziness, headache, tremor, diplopia and sedation have been evaluated and they can lead to the reduction or the discontinuation of the drug

Weight gain: being overweight at the beginning of treatment may be a significant predictor of further weight gain with VPA

Blood dyscrasias: different studies demonstrated the association of VPA with pro and anticoagulatory effects and they are dose-dependent

Endocrinological disorders: there is a correlation between hypothyroidism and treatment with VPA in monotherapy; moreover, VPA increases the synthesis of Testosterone and decreases its conversion to Estradiol, leading to the PCOS with amenorrhea and irregular periods

Hair loss: it is usually transient and sometimes dose-related. Regrowth normally begins within 6 months after the end of the therapy

Hypersensitivity: this effect is rare and dose, time, frequency-independent

Teratogenicity: despite VPA can induce teratogenic effects during pregnancy, United States Food and Drugs Administration considers acceptable the risk/benefit ratio. The most common teratogenic effect is the delay/impaired development

VPA: Valproic acid; PCOS: Polycystic ovary syndrome.